Combination Antifungal Therapy for Invasive Fungal Infections in Children and Adults

Nevin Hatipoglu; Husem Hatipoglu

Expert Rev Anti Infect Ther. 2013;11(5):523-535.

Basic Approaches to Combination Antifungal Therapy

The combined use of any two antifungal agents is determined by their desired and adverse features. Lessened possibility of resistance, decreased toxicity and synergistic effect when they are used in conjunction are the most common noticed advantages of combination therapy.^[3] On the other hand, drug-to-drug interactions, increased cost and toxicity, and most importantly, antagonistic interactions are disadvantages of such combinations.

Data about interactions between antifungal agents against mycoses are gathered from in vitro susceptibility testing and interactions between drugs, while relationships between fungal pathogens and host are explored by animal model studies. There have been numerous in vitro and animal studies performed on combination antifungal therapy. However, they have some limits, as the effects observed may not correspond to practice in the human body, but they are still necessary to outline original clinical trials. The strength and weakness of each type of study has been summarized in Table 1.

The studies in laboratory and animal models about pharmacodynamic properties of antifungal agents reveal that their use in combination usually displays both synergy and antagonism with the same antifungals.^[4] The disagreement may be due to there being no standardization between experimental methods in these studies. These reports also do not necessarily correlate with clinical setting, further complicating the interpretation of these data.

Double or triple combinations of antifungal drugs can exhibit complex interactions due to pharmacokinetic factors as well. Amphotericin B (AMB), voriconazole and caspofungin were used in vitro in different drug concentrations.^[5] Synergy was recorded in low drug levels, while higher drug concentrations demonstrated antagonism; which was explained by the different modes of action of each drug.

Administration of the same two antifungals can result in both wanted and unwanted effects that are attributable to pharmacokinetic issues. An example of this is the combined use of flucytosine (which reaches appreciable levels in all tissues, including cerebrospinal fluid [CSF]) with AMB (limited CSF penetration) in the treatment of cryptococcal meningitis (see below) results in faster sterilization of the CSF and fewer relapses compared with AMB monotherapy.^[6,7] Conversely, AMB-induced renal dysfunction can lead to the rapid accumulation of flucytosine, increasing the risk of hematological toxicity.^[8]

As the spectrum of activity for each antifungal agent is not the same, combination therapy may give the advantage of a broadened spectrum. Thus, the use of more than one antifungal agent is hoped to overcome any failure in empiric or pre-emptive therapy. On the other hand, the more drugs that are given empirically without any culture confirmation, the more difficult it is to decide which drug should be discontinued after the causative agent has been isolated.

Combination therapy for invasive fungal diseases has long been considered to minimize development of antifungal resistance, by extrapolating from the success of drug combinations against bacterial (e.g., enterococci), mycobacterial and some viral (e.g., HIV) infections. However, antifungal resistance and tolerance are weaker grounds for the empirical use of combination antifungal therapy. Antifungal-resistant isolates have been documented in patients with severe and long-lasting immune compromise, as well as after prolonged antifungal exposure.^[9,10] Nevertheless, it has yet not been confirmed that the development of resistant fungal pathogens can be avoided by the use of combination antifungal therapy. Treatment of invasive Candida infections with flucytosine monotherapy commonly leads to the easy emergence of resistant isolates. This problem can be overcome by addition of AMB to a flucytosine regimen. Unfortunately, combinations of major antifungals to lessen secondary antifungal resistance have not shown similar success.

Sometimes combination therapy is used to decrease the toxicity of a poorly tolerated agent while still maintaining its efficacy.^[11] AMB-based therapies carry the risk of nephrotoxicity.^[12] The combination of a newer triazole or echinocandin with conventional or a lipid formulation of AMB may enable us to lower the drug dosages and thus diminish the adverse event profile.^[3]

There are also some drawbacks of using antifungal combinations, the most serious of which is an increased risk of toxic effects. An example of this is mentioned above as concomitant use of AMB and flucytosine in cryptococcal meningitis.^[8,13]

Second, there is a greater chance of drug interactions. Azole antifungals (e.g., fluconazole, itraconazole and voriconazole) alter metabolism of cyclophosphamide, a cytotoxic agent, through differential inhibition of hepatic cytochrome P-450 isoenzymes, and can increase its toxicity when used in combination in immunosuppressed patients.^[14]

In addition, the use of drug combinations may produce a false sense of security, because the physician may feel that all possible pathogens are being covered.^[15] The final and perhaps most debatable negative aspect of combination antifungal therapy is the cost. Because at least two drugs are being administered combination therapy can push the cost as high as four- to eight-fold per day compared with monotherapy; this is the principal disadvantage and is discouraging its use.^[3]

There are numerous currently available antifungal agents. Agents altering the cellular membrane include azoles (fluconazole, miconazole, itraconazole, voriconazole and posaconazole) and polyenes (AMB and its lipid formulations).^[16] Flucytosine is an antimetabolite and inhibits the protein synthesis of the fungal cell. New additions include the echinocandins, namely caspofungin, micafungin and anidulafungin, acting by inhibition of 1,3-β-glucan synthase required for the formation of the cell wall.^[17] The addition of these new antifungals to other agents, effective at distinct targets, provides a paradigm of antifungal combinations for IFIs.^[18] The use and dosing of novel antifungals, such as posaconazole, anidulafungin and itraconazole, is not licensed for use in children. Voriconazole is limited to patients who are at least 2 years of age and caspofungin to 3 months and older.

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Next Section

Abstract and Introduction
Basic Approaches to Combination Antifungal Therapy
Mechanisms of Action of the Antifungal Agents
Combination Antifungal Drug Therapy in Selected Fungal Infections
Expert Commentary
Five-year View
References
Sidebar

Table 1. Summarized issues associated with various models of studies on combination antifungal therapy.
Category	Characteristics
	Strengths	Weaknesses
In vitro studies	Easily repeated, easily analyzed statistically, easily applied to multiple isolates, easy to study patterns of resistance	Host factors are ignored
Animal models	Host homogeneity can be provided, host factors are integrated, resistant isolates can be tested, quantitative end points (tissue burden and rate of clearance) can be stated	Poorly mimics human disease, the action and side effects of test drug in vivo may not imitate that in human body, limited numbers of repetitions are possible
Case reports	Sometimes relay unconventional practice	Usually restricted to infections with uncommon mycoses, intended to present eccentric experience, lack of comparator data limits interpretation of drug efficacy or safety
Clinical trials	Constitute a good reference for guidelines	Subjects and infecting isolates are heterogeneous, no ability to control nature of infecting isolate, comorbidity cannot be controlled, quantitative end points are frequently difficult to apply, dose verification is limited, multicentric, prospective and randomized experiences are needed, very expensive, slow to attain end point

Data taken from [3,18].

Table 2. Main mechanisms of action and examples of combination antifungal agents.
Mechanism of action	Result	Example	Interaction
Interruption in different stages of the same metabolic process	Blocking the synthesis of end product by various points	Both terbinafine and azoles inhibit ergosterol biosynthesis, resulting in disruption of fungal cell membrane and cell death	Synergy
Disruption of fungal cellular outer barrier (i.e., cell wall or membrane) by one agent	Facilitated entrance of another agent into fungal cell	Azoles and polyenes act on cell membrane and assist penetration of flucytosine, which inhibits nucleic acid synthesis and improves killing effect	Synergy
Activity on separate parts of fungal cell targets	Enforced attack on fungus	Candins destroy fungal cell wall and azoles and polyenes impair cell membrane, both leading to cell lysis	Synergy
Damaging part of fungus essential for the activity of the second antifungal agent	The second antifungal cannot exert its fungistatic/fungicidal effect	Azoles inhibit biosynthesis of ergosterol, which is necessary for polyenes to perform their antifungal activity	Antagonism
Change in composition of target by one antifungal	Next administration of another antifungal agent becomes ineffective	Ergosterol loses its original molecular configuration with previous exposure to azoles and successive use of AMB becomes dysfunctional	Antagonism

AMB: Amphotericin B.

Table 3. Indications of combination antifungal therapy according to guidelines by the Infectious Diseases Society of America.
Infection	Role of combination antifungal therapy	Strength of recommendation
HIV-associated cryptococcal meningitis	Preferred as induction therapy: AMB + flucytosine	A-I
	Alternative for induction therapy: (L-AMB or ABLC) + flucytosine	B-II
	As alternatives, for induction and consolidation therapy along with other regimens: AMB + fluconazole, fluconazole + flucytosine	B-I, B-II
Cryptococcal meningitis in transplant recipients	Induction therapy: L-AMB/ABLC + flucytosine	B-III
Cryptococcal meningitis in patients without HIV or transplant	Induction therapy: AMB + flucytosine	B-II
Candidemia, osteoarticular infections, esophagitis	Not recommended for routine management
CNS candidiasis	LFAB ± flucytosine	B-III
Candida endophthalmitis	AMB + flucytosine	A-III
Candida endocarditis or infected VAD, ICD or pacemaker	(LFAB/AMB) ± flucytosine	B-III
Invasive pulmonary aspergillosis	Primary therapy: not recommended for routine management
	Salvage therapy: could be considered	B-II

Table 4. Summary of clinical trials about antifungal combinations for invasive fungal infections in children.
Study (year)	Type of study	Patients (n)	Age	Underlying condition	Type of mycoses	Treatment	Outcome(s)	Adverse events	Ref.
Natarajan et al. (2005)	Retrospective	13	11–210 days	12 patients VLBW preterms in NICU	Candidemia	AMB and/or fluconazole or flucytosine plus caspofungin	Blood sterilization in 11 patients, seven patients died	Thrombophlebitis, hypokalemia, elevation of liver enzymes	^[42]
Burgos et al. (2008)	Retrospective	104 combination therapy population out of 131 patients	17 days–18 years	Malignancy, inherited immunodeficiency, HIV, transplant	Invasive aspergillosis	Any two or more of AMB, voriconazole, caspofungin, fluconazole, itraconazole, posaconazole, micafungin (not specifically reported)	No superiority of any one antifungal in terms of mortality	Not reported	^[58]
Nivoix et al. (2006)	Retrospective	Two pediatric subpopulation out of 17 patients	First patient: 3 years	Acute leukemia	First patient: chronic disseminated candidiasis	First patient: caspofungin and L-AMB or fluconazole	First patient: complete response	First patient: hepatotoxicity	^[73]
			Second patient: 15 years		Second patient: pulmonary aspergillosis	Second patient: caspofungin and voriconazole	Second patient: partial response	Second patient: not reported
Pancham et al. (2005)	Case reports	Three	Adolescents	Stem cell transplantation	Refractory fungal infections including Aspergillus fumigatus (two patients) and Candida krusei (one patient) candidemia	AMB and caspofungin	Improvement in two patients, death due to pulmonary hemorrhage in one patient	Not observed	^[79]
Cesaro et al. (2007)	Retrospective	40	1.2–17.9 years	Acute leukemia, lymphoma, myelodysplastic syndrome, nonmalignant disease	Invasive aspergillosis	Caspofungin and L-AMB or voriconazole	Favorable response rate of 53%	Bradiarrhythmia, diarrhea, bone pain, skin rash	^[80]
Yilmaz et al. (2011)	Retrospective	17	0.5–17 years	Neutropenia	Invasive fungal infection	Caspofungin and L-AMB or voriconazole	Favorable response rate of 68.4%, 12-week survival rate of 75%	No serious side effect	^[81]
Denning et al. (2006)	Prospective, multinational	Nine out of 225 adult and pediatric combination therapy population	3 months–16 years	Malignancy, stem cell/solid organ transplantation	Invasive aspergillosis	Micafungin and AMB (most patients) and/or an azole and/or caspofungin and/or flucytosine	Favorable response rate of 44.8%	Hepatotoxicity, gastro-intestinal side effects, hypertension; treatment stopped in 24.3% of pediatric patients	^[87]
Lehrnbecher et al. (2010)	Retrospective	Nine out of 15 combination therapy population	3.6–17.5 years	Malignancy, chronic granulomatous disease, diabetes mellitus	Disseminated candidiasis, invasive aspergillosis, zygomycosis	Posaconazole and AMB and/or caspofungin	Overall response of 60%	Abdominal side effects, headache, skin rash	^[100]