From the Department of Internal Medicine, Northeastern Ohio Universities Colleges of Medicine and Pharmacy, Rootstown and Infectious Disease Service, Summa Health System, Akron, OH.
Reprints: Anthony K. Leung, DO, Summa Physicians Infectious Disease, Suite 105, 75 Arch St, Akron, OH 44304. E-mail: email@example.com.
The author has no funding or conflicts of interest to disclose.
Written as an editorial commentary regarding Chaux, Combination Antifungal Therapy for Invasive Mold Infections Involving Polyenes, on pages 7-15 of the journal.
Combination therapy is a common practice for invasive diseases. For serious infections, combination therapy sometimes is used to improve efficacy and patient outcome. In certain infections, combination therapy has been proven to be effective and should be used whenever possible. For example, for enterococcal endocarditis, a β-lactam drug (such as ampicillin) plus an aminoglycoside (such as gentamicin or streptomycin) should be used whenever possible.1,2 In other circumstances, such as Pseudomonas bacteremia, the evidence to routinely support the practice might be controversial.3 Nevertheless, when considering combination therapy in whatever clinical settings, one needs to balance the strength of available evidence, potential benefits (or harm), and additional cost incurred.
Invasive fungal infections are a heterogeneous group of serious infections, and the patients who are most susceptible are those who are immunocompromised because of a hematological or oncological malignancy, have undergone hematopoietic stem cell or solid organ transplantations, have neutropenia because of recent chemotherapy, and are on high-dose corticosteroid for a variety of medical conditions. Invasive aspergillosis is one of those potentially serious infections. Aspergillus species are ubiquitous in the environment. The rarity of invasive diseases caused by the Aspergillus species among immunocompetent patients strongly suggests that intact host immunity is absolutely crucial to the control of this disease. Both the innate and adaptive immunities are needed to mount an adequate host response. Pathogen-associated molecular patterns such as Toll-like receptors and the lectinlike receptor dectin-1 engage fungal antigens, which in turn interact with neutrophils and macrophages to trigger intracellular signaling cascades to initiate production of various inflammatory cytokines and other fungicidal mechanisms. A fungal pathogen that escapes the innate mechanism will be encountered by the adaptive immune response. The fungal antigens are then processed by the dendritic cells and presented to helper T cells, which in turn results in either a TH1 or TH2 response elicited, depending on the pathogens.4
Certain antifungal drugs have immunomodulating properties, thus making combination therapy a theoretical sense.5 Amphotericin B deoxycholate (AmB-D) is known to be proinflammatory. A variety of inflammatory cytokines (tumor necrosis factor α, interleukin 6 [IL-6], IL-8, etc) are released from mononuclear cells and neutrophils after exposing to AmB-D in vitro.6,7 In a mice model study, AmB-D has been shown to induce TH1 response in mice with candidiasis.8 In contrast, different AmB formulations have different inflammatory cytokine response. For example, liposomal AmB was shown to induce a Toll-like receptor 4 response in neutrophils, and consequently, a more anti-inflammatory pattern of cytokines are produced.9 This property could potentially be exploited in settings where minimizing inflammatory tissue damage is vital. Echinocandins are a newer class of antifungal drugs that specifically inhibit the synthesis of 1,3-β-d-glucan of the fungal cell wall.10-12 Disruption of cell wall synthesis by this class of medication results in cell rupture and osmotic lysis. Recently, it was shown that when macrophages and monocytes were preexposed to an echinocandin, an enhanced inhibition of Aspergillus fumigatus was observed.13,14 Similarly, when Candida albicans was exposed to a sublethal concentration of caspofungin, unmasking of β-glucan was observed, and subsequently, a proinflammatory cytokine response was induced.15 Similar observations were made in other fungal species including other pathogenic molds such as Scedosporium apiospermum and Rhizopus oryzae. Echinocandins inherently have no activity against Zygomycetes. However, some recent reports indicated that a combination of echinocandin with another class of antifungal drug might be beneficial. In a mice model infected with disseminated R. oryzae, a combination of AmB liposomal complex with caspofungin improved the survival rate.16 About azoles, phagocytosis was shown to be enhanced when fluconazole or voriconazole was used against C. albicans when the phagocytes were activated by augmentative immune therapy such as granulocyte and/or granulocyte-monocyte colony-stimulating factor.17-19 These aforementioned immunomodulating properties are most certainly interesting and definitely warrant further clinical studies for effective application into clinical practice.
In this issue of Infectious Disease in Clinical Practice, Chaux shared the experience of combination antifungal therapy at his institution and illustrated some individual case studies or series on those patients. This topic has also been recently reviewed by Johnson et al.20 The reported results were encouraging and promising, but one needs to remember that this approach still by and large lacks strong evidence. It is still inherently very difficult to conduct such studies on human subjects. The pitfalls in designing and reviewing such studies were discussed in detail by Powers.21 The evidence for combination therapy is mostly limited to small case series and anecdotal reports. The heterogeneity of the patients and diseases make it difficult to interpret the results and translate the information into day-to-day clinical practice. For example, the efficacy of voriconazole, a new azole approved for invasive aspergillosis, was demonstrated in a total of 535 patients in 3 different studies.22-24 Only one of the studies had a comparator arm in it, which also had the most number of patients enrolled and was designed as a noninferiority trial.23
Is it time for infectious disease practitioners to consider a different treatment paradigm and think out of the box when treating such patients? Immunotherapy remains a relatively untapped area, and obviously, more studies need to be done to address this approach. As discussed previously, some antifungal drugs have immunomodulating properties, and theoretically, they can be used in the appropriate clinical settings to optimize clinical efficacy and minimize toxicity. Immunotherapeutics such as replacement immune therapies (eg, leukocyte transfusions), nonspecific augmentative immune therapies (eg, colony-stimulating factors, interferon gamma, and IL-12), and intravenous immunoglobulins have been used and described in the literature.25 Similar to combination antifungal therapies, the evidence in this area is weak, and more interdisciplinary translational research is needed.
In summary, combination antifungal therapy is a reasonable approach to patients with life-threatening invasive fungal infections. The evidence of such approach is still very limited, and clinicians need to consider the microbiological, pharmacological, and host factors in each individual case to come up with a thoughtful and sensible treatment plan.
1. Mandell GL, Kaye D, Levison ME, et al. Enterococcal endocarditis. An analysis of 38 patients observed at the New York Hospital-Cornell Medical Center. Arch Intern Med
2. Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Diseases Society of America. Circulation
3. Chamot E, Boffi El Amari E, Rohner P, et al. Effectiveness of combination antimicrobial therapy for Pseudomonas aeruginosa
bacteremia. Antimicrob Agents Chemother
4. Latge JP. Aspergillus fumigatus
and aspergillosis. Clin Microbiol Rev
5. Ben-Ami R, Lewis RE, Kontoyiannis DP. Immunocompromised hosts: immunopharmacology of modern antifungals. Clin Infect Dis
6. Cleary JD, Chapman SW, Nolan RL. Pharmacologic modulation of interleukin-1 expression by amphotericin B-stimulated human mononuclear cells. Antimicrob Agents Chemother
7. Wilson E, Thorson L, Speert DP. Enhancement of macrophage superoxide anion production by amphotericin B. Antimicrob Agents Chemother
8. Cenci E, Mencacci A, Del Sero G, et al. Induction of protective TH
1 responses to Candida albicans
by antifungal therapy alone or in combination with an interleukin-4 antagonist. J Infect Dis
9. Bellocchio S, Gaziano R, Bozza S, et al. Liposomal amphotericin B activates antifungal resistance with reduced toxicity by diverting Toll-like receptor signalling from TLR-2 to TLR-4. J Antimicrob Chemother
10. Mora-Duarte J, Betts R, Rotstein C, et al. Comparison of caspofungin and amphotericin B for invasive candidiasis. N Engl J Med
11. Ostrosky-Zeichner L, Kontoyiannis D, Raffalli J, et al. International, open-label, noncomparative, clinical trial of micafungin alone and in combination for treatment of newly diagnosed and refractory candidemia. Eur J Clin Microbiol Infect Dis
12. Krause DS, Reinhardt J, Vazquez JA, et al. Phase 2, randomized, dose-ranging study evaluating the safety and efficacy of anidulafungin in invasive candidiasis and candidemia. Antimicrob Agents Chemother
13. Chiller T, Farrokhshad K, Brummer E, et al. The interaction of human monocytes, monocyte-derived macrophages, and polymorphonuclear neutrophils with caspofungin (MK-0991), an echinocandin, for antifungal activity against Aspergillus fumigatus
. Diagn Microbiol Infect Dis
14. Choi JH, Brummer E, Stevens DA. Combined action of micafungin, a new echinocandin, and human phagocytes for antifungal activity against Aspergillus fumigatus
. Microbes Infect
15. Lamaris GA, Lewis RE, Chamilos G, et al. Caspofungin-mediated beta-glucan unmasking and enhancement of human polymorphonuclear neutrophil activity against Aspergillus
hyphae. J Infect Dis
16. Spellberg B, Fu Y, Edwards JE Jr, et al. Combination therapy with amphotericin B lipid complex and caspofungin acetate of disseminated zygomycosis in diabetic ketoacidotic mice. Antimicrob Agents Chemother
17. Garcha UK, Brummer E, Stevens DA. Synergy of fluconazole with human monocytes or monocyte-derived macrophages for killing of Candida
species. J Infect Dis
18. Baltch AL, Smith RP, Franke MA, et al. Effects of cytokines and fluconazole on the activity of human monocytes against Candida albicans
. Antimicrob Agents Chemother
19. Vora S, Purimetla N, Brummer E, et al. Activity of voriconazole, a new triazole, combined with neutrophils or monocytes against Candida albicans
: effect of granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor. Antimicrob Agents Chemother
20. Johnson MD, MacDougall C, Ostrosky-Zeichner L, et al. Combination antifungal therapy. Antimicrob Agents Chemother
21. Powers JH. Considerations in clinical trials of combination antifungal therapy. Clin Infect Dis
. 2004;39(suppl 4):S228-S235.
22. Perfect JR, Marr KA, Walsh TJ, et al. Voriconazole treatment for less-common, emerging, or refractory fungal infections. Clin Infect Dis
23. Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med
24. Denning DW, Ribaud P, Milpied N, et al. Efficacy and safety of voriconazole in the treatment of acute invasive aspergillosis. Clin Infect Dis
25. Casadevall A, Pirofski LA. Adjunctive immune therapy for fungal infections. Clin Infect Dis