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Combination therapy in invasive mucormycosis
*Corresponding author: Meera D. Shah, PharmD, BCIDP Department of Pharmacy Practice, University of the Incarnate Word, Feik School of Pharmacy, San Antonio, TX, USA. shahm500@gmail.com
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Received: ,
Accepted: ,
How to cite this article: Shah MD, Gibbons EA, Gutierrez GC. Combination therapy in invasive mucormycosis. Am J Pharmacother Pharm Sci 2025:014
Abstract
Objectives:
Mucormycosis is a rare and aggressive mold infection with an all-cause mortality of 54%. Treatment has historically been high-dose liposomal amphotericin B (LAmB) monotherapy. Recent data on combination therapies are conflicting, and their benefit remains unclear. This case series explores different combination therapies for mucormycosis and their effects on mortality.
Materials and Methods:
We report 17 cases of probable or proven mucormycosis managed with combination therapy for at least 48 h at University Hospital between March 2020 and November 2022.
Results:
The median age of patients was 60 years old (range 21–74), 11 patients were male (64.7%), and the median body mass index was 27.8 kg/m2. Of the 17 patients, all patients (100%) were Hispanic, nine patients (53%) had diabetes, and two patients (12%) were lung transplant recipients. The most common infection site was rhino-orbital (6/17; 35%), and surgery was performed on 11 patients (64.7%) after a median of 2 days after hospital admission. All 17 patients received LAmB with an average initial dose of 5.13 mg/kg/day (range 2.9– 6.4 mg/kg/day). All patients received combination therapy with either posaconazole (6/17; 35.2%), micafungin (4/17; 23.5%), or triple therapy (7/17; 41.2%). The duration of combination therapy was a median 6 days (range 2–21 days). Five of the 17 patients (29%) died of mucormycosis-related complications. Mortality observed in patients receiving combination therapy is as follows: micafungin combination (4/4; 100%), posaconazole combination (5/6; 83%), and triple therapy (0/7; 0%).
Conclusion:
Mucormycosis is an aggressive fungal infection with high morbidity and mortality requiring immediate recognition and medical intervention with an appropriate antifungal dosing regimen. Combination therapy with micafungin may be associated with higher mortality than posaconazole or triple therapy. In this cohort, combination therapy may have lower mortality than previously documented, but further investigation is needed to determine the optimal treatment for invasive mucormycosis.
Keywords
Amphotericin B/administration and dosage
Combination
Drug therapy
Fungal
Rhizopus
INTRODUCTION
Mucormycosis is a rare but aggressive mold infection caused by mucormycetes, which are present in the environment, particularly in soil and decaying organic matter. This invasive fungal infection is transmitted through inhalation, ingestion, or introduction of spores cutaneously and can cause tissue invasion and infarction secondary to angioinvasion.[1-3] Invasive mucormycosis (IM) is rare, so the exact number of cases are difficult to estimate; however, it is predicted that the prevalence is approximately 1.7 cases per million of U.S. population.[4,5] Prevalence is dependent on risk factors, including uncontrolled diabetes, trauma, burns, immunosuppression, chronic steroid use, and hematologic malignancies.[4]
Mortality for IM varies depending on the underlying patient condition, species of fungus, and affected body site. Despite aggressive antifungal treatment and immediate surgical intervention, the all-cause mortality rate of mucormycosis is 54%, but can be as high as 96% in disseminated infections.[6] Due to the rarity of this fungal infection in the U.S., the Infectious Disease Society of America does not have established guidance for the treatment of this fungal infection. Available guidelines include The European Conference on Infections in Leukemia (ECIL) from 2017 and The European Confederation of Medical Mycology (ECMM) from 2019.[7,8] Both guidelines strongly recommend high-dose liposomal amphotericin B (LAmB) as first-line treatment in adults with IM.[7,8]
Combination antifungal therapy is being explored as a potential treatment strategy for mucormycosis. Types of combination therapy under investigation include the LAmB backbone along with either azole or echinocandin therapy. In vitro and in vivo studies have shown that combination therapy may enhance the activity of antifungal agents against Mucorales and improve clinical outcomes.[9-14] The rationale for combination therapy is based on the synergistic or additive effects of antifungal agents with different mechanisms of action, which may enhance fungal cell wall damage, reduce resistance, and improve tissue penetration. Clinical data conducted to evaluate the safety and effectiveness of combination therapy for mucormycosis include small, retrospective, observational studies with conflicting results. Miller et al., found a trend toward lower mortality with combinations of LAmB and posaconazole or isavuconazole,[14] while other studies have not shown a mortality benefit with azoles or echinocandin combinations.[13] Due to a lack of definitive data to support combination therapy, the guidelines do not recommend combination therapy but state that it can be rationally given due to a lack of enhanced toxicity with possible but unproven benefit.[8] In summary, combination therapy may increase antifungal treatment efficacy and decrease mortality, but clinical data are inconclusive. The primary objective of this case series was to analyze antifungal dosing and mortality associated with various combination therapies.
MATERIALS AND METHODS
This retrospective case series included patients admitted to University Health in San Antonio, Texas, between March 2020 and November 2022 who were diagnosed with IM.[15] Patients were included if they had microbiologic data positive for Rhizopus spp., Mucor spp., Cunninghamella bertholletiae, Apophysomyces elegans, Lictheimia spp., Saksenaea spp., or Rhizomucor pusillus, and received LAmB plus an azole or echinocandin. Combination therapy included LAmB plus one of the followings in combination: posaconazole, micafungin, or both agents, defined as triple therapy. Combination therapy with any of the above regimens had to be continued for at least 48 h to be considered. The 2008 European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) consensus group definitions for invasive fungal disease (IFD) were used to classify IM. According to these criteria, proven IFD requires histopathologic evidence of fungal invasion of tissue or a positive culture from a normally sterile site. Probable IFD is defined by the presence of host factors, clinical features consistent with infection, and mycological evidence. All cases included in this study met criteria for either “probable” or “proven” IFD as per the consensus definitions.
Data extracted from the electronic medical record included patient demographics, underlying comorbidities, histopathological findings, prior antifungal use, co-infections, clinical manifestations, antifungal therapy, surgical intervention, and overall mortality. Risk factors for IM were also collected, including neutropenia (absolute neutrophil count <1,500/µL), lymphopenia, and diabetic ketoacidosis on admission. Clinical manifestations of IM were categorized as rhino-orbital-cerebral mucormycosis (ROCM), pulmonary, gastrointestinal, cutaneous, or disseminated. Disseminated IM was defined as 2 or more non-contiguous sites of involvement. Acute kidney injury (AKI) was defined as serum creatinine ×1.5 baseline within 1 week or an increase of 0.3 mg/dL within 48 h. Acute liver injury (ALI) was defined as liver function tests increase of ×5 upper limit of normal. Significant steroid use was defined as ≥600 mg of prednisone equivalent dose within 1 month of infection onset. These parameters were selected not only for their clinical relevance but also because of their association with medication safety, as renal and hepatic dysfunction, as well as corticosteroid exposure, may significantly influence antifungal drug metabolism, dosing, and toxicity.
RESULTS
In total, 17 patients had Mucorales-positive cultures or histopathology during the 33-month study period. After application of the EORTC/MSG criteria, 12 patients (70.6%) had proven fungal infection, and the remaining 5 patients (29.4%) had probable infection. Patient baseline demographics and clinical characteristics are displayed in Table 1. Overall, the median age at IM diagnosis was 60 years old, 65% were male, and all 17 patients were of Hispanic ethnicity. Two patients had an underlying malignancy, and more than half of the patients (52.9%) had diabetes mellitus, with two patients presenting with diabetic ketoacidosis. Two patients were solid organ transplant recipients who had received lungs in the previous 12 months. Three patients had a history of significant steroid use.
| Characteristic | Total (n=17) |
|---|---|
| Age, median in years (range) | 60 (21–74) |
| Male, n(%) | 11 (64.7) |
| Hispanic, n(%) | 17 (100) |
| BMI, median (range) | 27.8 (19.1–47.6) |
| BMI >30, n (%) | 4 (23.5) |
| Underlying malignancy, n(%) | 2 (11.8) |
| Other solid tumor malignancy | 2 (11.8) |
| Diabetes mellitus, n(%) | 9 (52.9) |
| Diabetic ketoacidosis on admission, n(%) | 2 (11.8) |
| Solid organ transplant, n(%) | 2 (11.8) |
| Lung transplant recipient | 2 (11.8) |
| History of significant steroid use, n(%) | 3 (17.6) |
| Azole prophylaxis due to lung transplant or history of mucormycosis, n(%) | 2 (11.8) |
BMI: Body mass index
Among patients with available Mucorales genus-level identification, the predominant genera were Rhizopus (10/17; 58.5%). The primary site of infection was largely rhino-orbital (6/17; 35.3%), followed by ROCM and pulmonary, with four patients each (4/17; 23.5%). Four patients were receiving mold prophylaxis with posaconazole or isavuconazole at the time of IM diagnosis. The duration for fungal prophylaxis ranged from 45 days to 2 years for various indications, such as lung transplant prophylaxis or history of mucormycosis. Coinfection with bacteria, fungi, and/or viruses was noted in 76.5% of patients. Of these, bacterial coinfections were the most common (70.6%; 12/13). Most of the patients received surgery for source control (11/17; 64.7%), with an average of 2 days from admission to the first surgery. Patients who did not receive source control through surgery were commonly patients with non-ROCM infections, such as pulmonary or gastrointestinal mucormycosis.
Combination therapy
All 17 patients received combination therapy for at least 72 h throughout the IM treatment course. However, the antifungals utilized in the combination therapy varied. Six patients (35.3%) received LAmB + posaconazole; four patients (23.5%) received combination therapy with LAmB and micafungin, and seven patients (41.2%) received all three agents (LAmB + posaconazole + micafungin) as triple therapy.
Antifungal dosing and adverse drug reactions
LAmB was most commonly dosed at 5–7.5 mg/kg/day using actual body weight throughout therapy. Five patients received subtherapeutic LAmB at <5 mg/kg/day at the beginning of therapy, which decreased to four patients by the end of LAmB therapy. Only one patient received high-dose LAmB at >7.5 mg/kg/day throughout the course of treatment. All patients who received posaconazole received an appropriate load of 300 mg twice daily ×2 doses, and then 300 mg daily for the remainder of the course. Micafungin was appropriately dosed at 100–150 mg daily. Thirteen patients (76.5%) developed AKI, while two of these 13 patients who received an azole had ALI.
Mortality
All-cause mortality after IM diagnosis was 29.4% (5/17) at 30 days within the total cohort. Of these five deceased patients, one patient had gastrointestinal IM (100%), one had cutaneous (50%), one had rhino-orbital (16.7%), and two patients had pulmonary IM (50%) [Table 2]. When analyzing mortality based on the type of combination therapy received, 1/6 (17%) of the LAmB + posaconazole combination group died, 4 (100%) of the LAmB + micafungin combination group died, and no patient in the triple therapy combination group died [Table 3 and Figure 1].
| Characteristic | Total (n=17) |
|---|---|
| Proven infection, n(%) | 12 (70.6) |
| Pathogen, n(%) | |
| Rhizopus spp. | 10 (58.5) |
| Rhizomucor spp. | 2 (11.8) |
| Other or unknown spp. | 5 (29.4) |
| Primary site of infection, n(%) | |
| Rhino-orbital | 6 (35.3) |
| Rhino-orbital cerebral | 4 (23.5) |
| Pulmonary | 4 (23.5) |
| Cutaneous | 2 (11.8) |
| Gastrointestinal | 1 (5.9) |
| Fungal prophylaxis received before IM, n(%) | 4 (23.5) |
| Posaconazole | 3 (17.6) |
| Isavuconazole | 1 (5.9) |
| Coinfection during hospitalization, n(%) | 13 (76.5) |
| Bacterial | 12 (70.6) |
| Viral | 1 (5.9) |
| Fungal | 1 (5.9) |
| Surgery received, n(%) | 11 (64.7) |
| Days from admission to surgery, median (range) | 2 (0–19) |
IM: Invasive mucormycosis
| Characteristic | Total (n=17) |
|---|---|
| LAmB | |
| Initial LAmB dosing, n(%) | |
| <5 mg/kg/day | 5 (29.4) |
| 5–7.5 mg/kg/day | 12 (70.6) |
| >7.5 mg/kg/day | 0 (0) |
| Final LAmB dosing, n(%) | |
| <5 mg/kg/day | 4 (23.5) |
| 5–7.5 mg/kg/day | 13 (76.5) |
| >7.5 mg/kg/day | 0 (0) |
| Maximum LAmB dosing throughout therapy, mg/kg/day, median (range) | 5.6 (3.1–8.7) |
| Total LAmB duration, days, median (range) | 12 (1–76) |
| Combination therapy | |
| Combination therapy received, n(%) | 17 (100) |
| LAmB+posaconazole | 6 (35.3) |
| LAmB+isavuconazole | 0 (0) |
| LAmB+micafungin | 4 (23.5) |
| Triple therapy | 7 (41.2) |
| Duration of combination therapy, median days (range) | 6 (2–19) |
| Acute kidney injury while on LAmB therapy, n(%) | 13 (76.5) |
| Acute liver injury while on azole therapy, n(%) | 2/13 (15.4) |
LAmB: Liposomal amphotericin B
- Suvival versus mortality based on combination therapy.
DISCUSSION
This case series evaluates various combination therapies for mucormycosis, including triple therapy, which presents an opportunity to assess the mortality benefit in the treatment of this complex infection.
Antifungal dosing
Guidelines published by ECMM and ECIL study groups continue to recommend the use of LAmB as first-line therapy. However, the dosing of this life-saving antifungal remains controversial. ECMM recommends 5–10 mg/kg for most patients, with 10 mg/kg recommended in the case of central nervous system involvement. The Ambizygo study found that higher doses of 7.5–10 mg/kg/day as first-line treatment for IM resulted in a 43% (12/28) response rate during the 1st week compared with 0% (0/5) in patients who received lower doses. However, 40% of the high-dose group experienced significant renal function. High LAmB dosing at 10 mg/kg/day, combined with surgery in 71% of cases, led to an overall response rate of 36% at week 4 and 45% at week 12. This study showed that promoting higher doses of 7.5–10 mg/kg/day can lower mortality but can cause subsequent renal impairment.[16-18]
In our study, LAmB dosing was less than ideal, with 29.4% of patients receiving subtherapeutic dosing at <5 mg/kg/day. By the end of therapy, a concerning 5/17 (23.5%) of patients were still receiving this suboptimal dosing. Of these five patients, two patients died (40%). No patients received the higher dosing at 7.5 mg/kg/day of this first-line agent at the start or end of the treatment course. This represents a hesitancy providers may have to start higher doses of this nephrotoxic agent, though appropriate dosing has been shown to benefit survival.[16,18]
Mortality
Mortality rate from mucormycosis varies depending on the underlying patient condition, species of fungus, and affected body site. Overall, the all-cause mortality rate of mucormycosis infections is 54% but can be as high as 96% in disseminated infections.[6] In our study, all-cause mortality was lower than previously documented in literature, at 29.4%. This difference could be due to the high percentage of patients with ROCM disease and the high surgical intervention rates that typically follow those patients. All our 17 patients receiving combination therapy could also contribute to the low mortality rate. Three of the five patients who died received surgical debridement.
Several clinical trials have been conducted to evaluate the safety and efficacy of combination therapy for mucormycosis. Reed et al., showed a significant benefit with LAmB plus an echinocandin therapy for ROCM in regard to cure rate and mortality.[12] However, limitations of this study, such as differences in baseline characteristics and analyzing only ROCM patients, make the results hard to generalize.[12] Kyvernitakis et al., found no survival benefit at 6 weeks when using LAmB with posaconazole, LAmB with echinocandins, or triple therapy with all three agents.[13] However, the combination therapy had a higher severity of illness, potentially preventing a difference from being seen.[13] Finally, Miller et al., showed a trend toward lower mortality in the combination group in a small sample size.[14] LAmB has been the backbone for mucormycosis treatment for decades, but there is conflicting evidence for combination therapy in these high-risk patients. The optimal combination, dosing, duration, and safety of these regimens remain unclear. Moreover, the lack of large, randomized controlled trials and standardized treatment protocols limits the generalizability and applicability of current evidence.
Our study found multiple clinically relevant trends when analyzing mortality based on the type of combination received. Patients who received triple therapy may be associated with the lowest mortality rate, with no patients dying after receiving all three antifungals for ≥48 h. In addition, combination therapy with micafungin may be associated with higher mortality compared to posaconazole or triple therapy [Table 4]. Whether combination therapy should be routinely considered an initial therapy should be determined on a case-by-case basis; however, this study has shown clinical trends toward a lower mortality in combination therapy with posaconazole, as well as in triple therapy.
| Mortality | Mortality based on treatment, n(%) |
|---|---|
| Overall mortality, n(%) | 5 (29.4) |
| Mortality of LAmB+posaconazole group, n(%) | 5/6 (83.3) |
| Mortality of LAmB+micafungin group, n(%) | 4/4 (100) |
| Mortality of triple therapy group, n(%) | 0/7 (0) |
LAmB: Liposomal amphotericin B
Limitations
There are several important limitations to our study. First, this study was a retrospective, case series using electronic health record data. Due to the nature of the study, causation cannot be inferred. In addition, the small sample size limited the ability to compare outcomes by therapy received. We were also unable to control for potential confounders, such as the severity of illness.
CONCLUSION
Despite the conflicting data for combination therapy in IM, our preliminary data provide evidence that combination therapy may be associated with lower mortality than previously documented in literature. Triple therapy may be associated with lower mortality than other combinations, and micafungin combinations may be associated with an increased mortality. Due to a lack of larger studies to show mortality benefit, this study provides a clinically relevant association that triple therapy with surgical intervention can increase survivability in patients with mucormycosis. However, larger studies are needed to confirm these conclusions.
Ethical approval:
Institutional Review Board approval is not required.
Declaration of patient consent:
Patient’s consent not required as there are no patients in this study.
Conflicts of interest:
There are no conflicts of interest.
Use of artificial intelligence (AI)-assisted technology for manuscript preparation:
The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript, and no images were manipulated using AI.
Financial support and sponsorship: None.
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