What is the evidence supporting combination therapy with amphotericin B and either azole antifungals or echinocandins for the treatment of mucormycosis?

Introduction

Mucormycosis (previously called zygomycosis) is a rare and aggressive fungal infection caused by molds most commonly in the Rhizopus and Mucor species.¹ The disease is spread through inhalation of, or contact with, the fungal spores. An analysis of 929 mucormycosis cases reported from 1940 through 2003 showed that the most common risk factor for the disease was diabetes mellitus, which was observed in 36% of cases, followed by hematologic malignancies (17%) and solid organ or hematopoietic cell transplantation (12%).² Other major risk factors include long-term corticosteroid use, neutropenia, injection drug use, hemochromatosis, skin injury, and cancer.¹ There are 5 types of mucormycosis: rhinocerebral, pulmonary, gastrointestinal, cutaneous, and disseminated. Clinical presentation of the disease depends on the location in which the infection manifests. For instance, patients with rhinocerebral mucormycosis typically present with symptoms similar to sinusitis, including sinus congestion, fever, and headache, while patients with pulmonary mucormycosis may experience symptoms such as fever, cough, and shortness of breath. Mortality also varies by site of infection; an overall mortality rate of 54% has been reported in literature despite adequate treatment with antifungal agents and/or surgery.² High mortality rates necessitate the use of unique approaches for treating this rare yet deadly disease. The purpose of this FAQ is to describe literature on the use of combination therapy with amphotericin B and either azole antifungals or echinocandins for treatment of mucormycosis.

Treatment of mucormycosis

The general approach to managing mucormycosis involves surgical debridement of affected tissues in conjunction with antifungal therapy.³ According to the 2014 Infectious Diseases Society of America (IDSA) practice guidelines for the diagnosis and management of skin and soft tissue infections, initial antifungal therapy options for Mucor/Rhizopus infections include lipid formulation amphotericin B (strong recommendation, moderate-quality evidence) or posaconazole, an azole antifungal agent (strong recommendation, low-quality evidence).⁴ The addition of an echinocandin could be considered based on synergy seen in murine models and observational clinical data (weak recommendation, low-quality evidence). The guidelines do not provide an elaborate discussion on combination therapy with echinocandins, nor comment on the use of combination treatment of amphotericin B with azole antifungals. Additionally, the 2016 National Comprehensive Cancer Network (NCCN) guidelines for prevention and treatment of cancer-related infections do not provide recommendations for the use of combination therapies of amphotericin B with azoles or echinocandins to treat mucormycosis.⁵ The NCCN guidelines recommend use of isavuconazole or posaconazole as maintenance treatment for mucormycosis following control of infection with amphotericin B and/or surgical debridement. The use of echinocandins as individual agents for treatment is not discussed. No other national organizations have published relevant guidelines that discuss the treatment of mucormycosis, including combination antifungal therapies.

The European Society for Clinical Microbiology and Infectious Diseases (ESCMID) and European Confederation of Medical Mycology (ECMM) jointly published clinical guidelines for the diagnosis and management of mucormycosis in 2013.⁶ In the guidelines, combination treatment with lipid-based amphotericin B and caspofungin (an echinocandin) is listed among the first-line treatment options for mucormycosis for both adults and pediatric patients (including neonates). In pediatric patients, the combination of lipid amphotericin B plus caspofungin, and the combination of lipid amphotericin B plus posaconazole for children ≥2 years of age, are also recommended as salvage therapy options. Indications for salvage treatment include refractory disease or intolerance towards previous antifungal therapy, or a combination of both. All recommendations in this guideline regarding these combination treatments are of marginal strength and based on evidence from clinical experience, descriptive case studies, opinions of respected authorities, or reports of expert committees.

Studies on combination antifungal treatment for mucormycosis

A review of literature identified 20 studies on the use of antifungal combination therapy for mucormycosis; these studies are summarized in Table 1.^7-26 There were roughly similar numbers of reports on children and adults, as well as male and female patients. In terms of risk factors for mucormycosis, almost all patients had either poorly controlled diabetes, or were on immunosuppressive or chemotherapy agents. Approximately half of the cases involved a diagnosis of rhinocerebral mucormycosis; gastrointestinal mucormycosis was the second most common type of infection. A large majority of patients received surgical resection in addition to combination antifungal treatment. Across the literature, the study outcomes were categorized as treatment success, regression of disease, or failure; outcome definitions were not sufficiently reported.

Eight case reports described combination treatment with amphotericin B and an azole antifungal.^7-14 Seven case reports, 1 case series, 1 prospective study, and 1 retrospective review described treatment with amphotericin B and an echinocandin.^15-24 Two case reports described use of all 3 antifungal agents (ie, amphotericin B, azole antifungal, and echinocandin).^25,26 The most commonly used azole antifungal was posaconazole while the most commonly used echinocandin was caspofungin. Treatment success (n=12 studies) or regression of disease (n=3) was observed in most studies, regardless of the type of combination used. One case report was identified that used isavuconazole in combination with amphotericin B; this combination failed to treat the infection. One study used micafungin plus amphotericin B and was successful in treating the infection. The 2 studies that used triple antifungal therapy both resulted in treatment success.

Table 1. Cases of combination therapy with amphotericin B and either azole antifungals or echinocandins for the treatment of mucormycosis.^7-26

Conclusion

Existing literature provides mixed results regarding the efficacy of treating mucormycosis with the combination of amphotericin B with either azole antifungals or echinocandins, although successful combination treatments have been described. The identified studies (mostly case reports) demonstrate that the combination of amphotericin B plus posaconazole has resulted in treatment success most frequently. However, due to the weak nature of the evidence, it is difficult to conclude that this particular combination is recommended for all patients or types of mucormycosis infections. There are several limitations to the evidence. In addition to the small number of patients, most patients underwent surgical debridement, making it difficult to assess the true impact of combination antifungal treatment on outcomes. Other patient-specific factors, such as the presence or absence of neutropenia, may have also influenced the response to antifungal therapy. Of note, it is possible that some publications may not have been identified through the search strategy and review process utilized; studies published in languages other than English were not included.

Amphotericin B continues to be the recommended first-line treatment for mucormycosis across clinical guidelines.^4-6 Both echinocandins (caspofungin, micafungin) and the azole antifungals (posaconazole, isavuconazole) used in the studies have generally safe pharmacologic profiles and cause minimal adverse effects.^27,28 Since mucormycosis is a serious and deadly disease, combination therapy may be deserving of an attempt when amphotericin B monotherapy is inadequate. However, more robust studies are needed to further elucidate where this treatment strategy may fit into the management of mucormycosis.

References

1. Mucormycosis. Centers for Disease Control and Prevention. Updated February 25, 2021. Accessed April 25, 2022. https://www.cdc.gov/fungal/diseases/mucormycosis/index.html
2. Roden MM, Zaoutis TE, Buchanan WL, et al. Epidemiology and outcome of zygomycosis: a review of 929 reported cases. Clin Infect Dis. 2005;41(5):634-653. doi:10.1086/432579
3. Cox GM, Kauffman CA, Hall KK. Mucormycosis (zygomycosis). UpToDate. UpToDate; 2022. Accessed April 27, 2022. https://www.uptodate.com/contents/mucormycosis-zygomycosis?search=mucormycosis&source=search_result&selectedTitle=1~83&usage_type=default&display_rank=1#H1297153698
4. Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America [published correction appears in Clin Infect Dis. 2015 May 1;60(9):1448. Dosage error in article text]. Clin Infect Dis. 2014;59(2):e10-e52. doi:10.1093/cid/ciu444
5. Baden LR, Swaminathan S, Angarone M, et al. Prevention and treatment of cancer-related infections, version 2.2016, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2016;14(7):882-913. doi:10.6004/jnccn.2016.0093
6. Cornely OA, Arikan-Akdagli S, Dannaoui E, et al. ESCMID and ECMM joint clinical guidelines for the diagnosis and management of mucormycosis 2013. Clin Microbiol Infect. 2014;20 Suppl 3:5-26. doi:10.1111/1469-0691.12371
7. Lango-Maziarz A, Kołaczkowska M, Siondalski P, Duda M, Dubowik M, Lango R. Colon mucormycosis with renal spread resistant to lipid complex amphotericin and isavuconazole treatment in a heart transplant recipient. Pol Arch Intern Med. 2022;132(1):16156. doi:10.20452/pamw.16156
8. Salehi M, Shahi F, Rizvi FS, et al. Combination antifungal therapy without craniotomy in an immunocompromised patient with rhino-orbito-cerebral mucormycosis: a case report. Caspian J Intern Med. 2020;11(2):227-230. doi:10.22088/cjim.11.2.227
9. Athanasiadou KI, Athanasiadis DI, Constantinidis J, Anastasiou A, Roilides E, Papakonstantinou E. Successful treatment of rhinoorbital mucormycosis due to Rhizopus arrhizus with liposomal amphotericin B, posaconazole and surgical debridement in a child with neuroblastoma. Med Mycol Case Rep. 2019;25:10-14. doi:10.1016/j.mmcr.2019.06.003
10. Mardani M, Yadegarynia D, Tehrani S. Combination antifungal treatment for sino-orbito-cerebral mucormycosis: a case report. Arch Clin Infect Dis. 2016;11:e28345. doi:10.5812/archcid.28345
11. Ville S, Talarmin JP, Gaultier-Lintia A, et al. Disseminated mucormycosis with cerebral involvement owing to rhizopus microsporus in a kidney recipient treated with combined liposomal amphotericin B and posaconazole therapy. Exp Clin Transplant. 2016;14(1):96-99. doi:10.6002/ect.2014.0093
12. Ebadi M, Alavi S, Ghojevand N, Aghdam MK, Yazdi MK, Zahiri A. Infantile splenorenopancreatic mucormycosis complicating neuroblastoma. Pediatr Int. 2013;55(6):e152-e155. doi:10.1111/ped.12182
13. Katta J, Gompf SG, Narach T, et al. Gastric mucormycosis managed with combination antifungal therapy and no surgical debridement. Infect Dis Clin Pract. 2013;21(4):265–268. doi:10.1097/IPC.0b013e31826e81b3
14. Rickerts V, Atta J, Herrmann S, et al. Successful treatment of disseminated mucormycosis with a combination of liposomal amphotericin B and posaconazole in a patient with acute myeloid leukaemia. Mycoses. 2006;49(1):27-30. doi:10.1111/j.1439-0507.2006.01299.x
15. Khera S, Singh V, Pattanayak S. Favourable outcome in a child with acute lymphoblastic leukaemia and pulmonary mucormycosis managed with combination antifungal therapy of liposomal amphotericin B and caspofungin. BMJ Case Rep. 2021;14(10):e245329.. doi:10.1136/bcr-2021-245329
16. Gargouri M, Marrakchi C, Feki W, et al. Combination of amphotericin B and caspofungin in the treatment of mucormycosis. Med Mycol Case Rep. 2019;26:32-37.. doi:10.1016/j.mmcr.2019.09.006
17. Wang XM, Guo LC, Xue SL, Chen YB. Pulmonary mucormycosis: a case report and review of the literature. Oncol Lett. 2016;11(5):3049-3053. doi:10.3892/ol.2016.4370
18. Kazak E, Aslan E, Akalın H, et al. A mucormycosis case treated with a combination of caspofungin and amphotericin B. J Mycol Med. 2013;23(3):179-184. doi:10.1016/j.mycmed.2013.06.003
19. Ogawa T, Takezawa K, Tojima I, et al. Successful treatment of rhino-orbital mucormycosis by a new combination therapy with liposomal amphotericin B and micafungin. Auris Nasus Larynx. 2012;39(2):224-228. doi:10.1016/j.anl.2011.03.006
20. Phulpin-Weibel A, Rivier A, Leblanc T, Bertrand Y, Chastagner P. Focus on invasive mucormycosis in paediatric haematology oncology patients: a series of 11 cases. Mycoses. 2013;56(3):236-240. doi:10.1111/myc.12010
21. Ojeda-Uribe M, Herbrecht R, Kiefer MH, et al. Lessons from a case of oromandibular mucormycosis treated with surgery and a combination of amphotericin B lipid formulation plus caspofungin. Acta Haematol. 2010;124(2):98-102. doi:10.1159/000315675
22. Reed C, Bryant R, Ibrahim AS, et al. Combination polyene-caspofungin treatment of rhino-orbital-cerebral mucormycosis. Clin Infect Dis. 2008;47(3):364-371. doi:10.1086/589857
23. Nivoix Y, Zamfir A, Lutun P, et al. Combination of caspofungin and an azole or an amphotericin B formulation in invasive fungal infections. J Infect. 2006;52(1):67-74. doi:10.1016/j.jinf.2005.01.006
24. Voitl P, Scheibenpflug C, Weber T, Janata O, Rokitansky AM. Combined antifungal treatment of visceral mucormycosis with caspofungin and liposomal amphotericin B. Eur J Clin Microbiol Infect Dis. 2002;21(8):632-634. doi:10.1007/s10096-002-0781-6
25. Pomorska A, Malecka A, Jaworski R, et al. Isavuconazole in a successful combination treatment of disseminated mucormycosis in a child with acute lymphoblastic leukaemia and generalized haemochromatosis: a case report and review of the literature. Mycopathologia. 2019;184(1):81-88. doi:10.1007/s11046-018-0287-0
26. Roux BG, Méchinaud F, Gay-Andrieu F, et al. Successful triple combination therapy of disseminated absidia corymbifera infection in an adolescent with osteosarcoma. J Pediatr Hematol Oncol. 2010;32(2):131-133. doi:10.1097/MPH.0b013e3181ca0dcf
27. Lewis RE, Kauffman CA, Bogorodskaya, M. Pharmacology of echinocandins. UpToDate. UpToDate; 2022. Accessed May 4, 2022. https://www.uptodate.com/contents/pharmacology-of-echinocandins?csi=96a16bb8-5c4c-4d11-896f-e672c2d7a78a&source
28. Ashely ED, Perfect JR, Kauffman CA, Bogorodskaya, M. Pharmacology of azoles. UpToDate. UpToDate; 2022. Accessed May 4, 2022. https://www.uptodate.com/contents/pharmacology-of-azoles?topicRef=13945&source

Prepared by:
Tiffany Kuo
PharmD Graduate Class of 2022
University of Illinois at Chicago College of Pharmacy

Edited by:
Honey Joseph, PharmD
PGY2 Drug Information Resident
University of Illinois at Chicago College of Pharmacy

July 2022

The information presented is current as May 4, 2022. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.