Combination Antifungal for Invasive Mucormycosis: Yay or Nay?

This photomicrograph revealed ultrastructural morphology exhibited by a columella of the fungal organism, Rhizopus oryzae, also known as Rhizopus arrhizus var. delemar. This organism is known to be an opportunistic pathogen in humans causing the disease known as mucormycosis.

Mucormycosis continues to place a significant burden on high-risk patient populations, such as those with immunocompromising conditions or diabetes mellitus.¹ Although the overall incidence is relatively low, morbidity and mortality associated with mucormycosis remain unacceptably high.² Early identification has been associated with improved outcomes but can be challenging given the complex interplay of host factors and diagnostic criteria.^3,4 Surgery and antifungal therapy are considered mainstays of treatment, but their impact can be limited in more severe cases of disseminated disease.^1,5

Historically, amphotericin B (AMB) was the only antifungal agent available with in vitro activity against members of the Mucorales order. Despite the approval of additional Mucorales-active agents such as posaconazole and isavuconazole, as well as improvements in diagnostic modalities for invasive mucormycosis (e.g. nucleic acid sequencing), mortality for this disease has remained high.^1,6,7 One management strategy that has been explored is combination antifungal therapy. Data from both in vitro and clinical studies pertaining to the subject are conflicting with respect to potential benefits of this strategy. Recent guidelines provide only a marginal recommendation for its use, based primarily on the lack of a signal for enhanced toxicity.⁵ As such, the role of combination antifungal therapy for invasive mucormycosis remains unclear.

IN VITRO DATA

Despite the individual in vitro activities of AMB and the newer azole antifungals against Mucorales, combination use of these agents in animal studies have led to mixed findings. One study in a neutropenic murine model of disseminated mucormycosis found that the combination of low-dose AMB and posaconazole was effective for prolonging survival as well as reducing fungal load within renal tissue, but accomplished this to a degree similar to that of high-dose AMB alone.⁸ For one strain of Rhyzopus oryzae, low-dose AMB and posaconazole was superior at reducing fungal load within brain tissue when compared to high-dose AMB alone. Interestingly, superiority was not replicated with the combination of high-dose AMB and posaconazole. A similar study looking at disseminated mucormycosis in a neutropenic murine model found no difference in tissue fungal burden reduction nor time to death between liposomal amphotericin B (LAmB) and combination posaconazole and LAmB.⁹ These results were reflected in the diabetic ketoacidosis (DKA) murine model analyzed as well.⁹ Based on the findings of these animal studies, it is unclear what benefit combination therapy with AMB and posaconazole may have in clinical cases of mucormycosis.

Although echinocandins lack significant activity against Mucorales in vitro, their role in combination therapy has been explored in several animal studies. One such study utilized a combination of amphotericin B lipid complex (ABLC) with either micafungin or anidulafungin in a DKA murine model.¹⁰ The combination of ABLC and low-dose micafungin improved survival compared to monotherapy with either agent alone, but the high-dose micafungin/ABLC combination did not show similar results. In contrast, high-dose anidulafungin in combination with ABLC led to improved survival compared to monotherapy with either agent alone, but low-dose anidulafungin/ABLC did not. It is unclear why there seems to be a differential (and paradoxical) dose-dependent synergism with polyene/echinocandin therapy, but these findings suggest that treatment of disseminated mucormycosis with combination therapy may lead to improved outcomes.

CLINICAL DATA

Given the relatively low incidence and diagnostic complexity of invasive mucormycosis, it has been difficult to directly evaluate the effect of combination antifungal therapy on patient outcomes. Several studies from the early-to-middle 2000s have indirectly commented on the impact of combination antifungal therapy and suggested that there may be little or no benefit from its use for invasive mucormycosis.^11–13 However, these studies were not initially designed to evaluate combination therapy and there was likely a large degree of selection bias present, primarily seen as increased disease severity for patients who were treated with combination therapy.

A clinical study conducted by Reed and colleagues was able to show a statistically significant benefit of using combination antifungal therapy over monotherapy for invasive mucormycosis.¹⁴ They observed an improvement in 30-day success with up-front combination polyene/echinocandin when compared to polyene monotherapy for patients with rhino-orbital-cerebral mucormycosis (ROCM). However, since the study population only comprised patients with ROCM, the results lack generalizability to those with other forms of invasive mucormycosis.

Additionally, their study population consisted of at-risk patients primarily due to a history of diabetes with limited inclusion of neutropenic patients and transplant recipients. Given the relative importance of immune cells in protecting against invasive fungal infections, the results of this study may not be as applicable to the broader population who have relatively higher degrees of immunosuppression and rates of mortality.¹⁵

Another major obstacle in the study of combination therapy for invasive mucormycosis has been the staggered introduction of newer antifungal agents to the market during the early 2000s, which has complicated attempts at comparing groups in an unbiased fashion. Findings from a retrospective study spanning 1995 to 2011 by Abidi and colleagues suggested a lack of improvement for overall survival in patients treated with combination therapy versus monotherapy for invasive mucormycosis.¹⁶ However, the division of the cohorts was temporally based on the approval of voriconazole, which makes it difficult to directly compare results when caspofungin was approved before voriconazole while posaconazole was approved afterwards.

Additionally, patients were primarily treated with monotherapy in both arms, which may have masked any differential effect of combination therapy. Kyvernitakis and colleagues conducted a study with a similar temporal design but had focused their efforts on studying the effect of initial combination therapy directly.¹⁷ After propensity score adjustments, the authors found no difference in mortality at 6 weeks and 12 weeks for combination vs monotherapy for invasive mucormycosis. Despite the concerted efforts of the authors at temporally controlling for antifungal commercial availability in these studies, other differences between time periods still persisted, such as diagnostic capabilities and surgical techniques, making it difficult to clearly interpret outcomes.

Miller and colleagues conducted a more recent study that took a slightly different methodological approach by utilizing a primary endpoint of treatment failure (comprising mortality or a need to change antifungal therapy) as well as incorporating a desirability of outcome ranking analysis for treatment failure.¹⁸ No significant difference was found between combination therapy and monotherapy for invasive mucormycosis, but a higher proportion of patients benefited from combination therapy compared to those who received monotherapy. One limitation to note in this study, as well as the prior studies of combination antifungal therapy for mucormycosis, is the lack of a standardized definition of combination therapy (e.g. duration), which further complicates interpretation of potential benefits.

CONCLUSION

The impact of combination antifungal therapy for invasive mucormycosis has been difficult to ascertain. Animal studies suggest some potential benefit, but results are inconsistent and may depend on antifungal choice as well as dose. Many retrospective studies have attempted to assess clinical impact but show discordant results and have been largely challenged by advancements in diagnostics, surgical procedures, and antifungal agents. Despite this equivocal benefit, combination antifungal therapy is still often utilized for these challenging cases. Larger and ideally prospective trials are needed to more definitively address this clinical question. Although the low incidence of invasive mucormycosis may make this difficult to achieve, increased uptake of novel diagnostics and utilization of fungal registries may hold promise for future studies.

References

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