Cryptococcosis is a global invasive mycosis associated with significant morbidity and mortality, especially in HIV-infected populations, thus combination antifungal therapy is universally recommended as essential for a successful outcome. Flucytosine is a small water-soluble antifungal that distributes widely and rapidly enters the CSF; this feature renders it a good agent for intracranial mycotic infections. Conversely, its use as monotherapy has been associated with rapid development of resistance, comprising the basis for its concurrent use in cryptococcal meningitis.
Combination of flucytosine and AMB has been investigated extensively in in vitro studies and was found not to be particularly effective against Cryptococcus neoformans isolates; however, prolonged survival and/or reduction in tissue burden were observed in animal models. For HIV-and non-HIV-associated cryptococcal meningitis, this combination is preferred as the initial (induction) therapy. Other combinations proposed as alternative therapies include AMB plus fluconazole or fluconazole plus flucytosine as induction therapy for cryptococcal meningitis.
Cryptococcosis occurs less frequently in children, and this population has more characteristic risk groups for this infection, such as primary immunodeficiencies and certain malignancies (e.g., acute lymphoblastic leukemia). Treatment of disseminated and CNS disease in pediatric age constitutes AMB and flucytosine combination as induction and consolidation, followed by fluconazole as maintenance therapy.[6,24] Unfortunately, optimal duration of therapy and pediatric dosing have not been determined precisely.
Candida species are the most common cause of invasive fungal infections, ranging from superficial mucocutaneous disorders to life-threatening disease that can lead to severe organ damage. Bloodstream infections caused by Candida spp. can be treated with several antifungal agents effectively when applied for a satisfactory time period. Consequently, the routine use of combination therapy for candidemia is not advised. This approach is usually considered in difficult individual settings, that is, chronic disseminated candidiasis. There are only examples of anecdotal case reports and open-label series in which combination therapy has been considered, such as hepatosplenic candidiasis, candidal endocarditis,[26,27] meningitis, endophthalmitis[29,30] and peritonitis.[31,32]
Antifungal combinations may show different activity in different sites of the body. Non-neutropenic intensive care patients with invasive candidal infection were treated either with AMB plus flucytosine or fluconazole monotherapy. Clinical outcome was similar in both treatment groups when the infection type was candidal pneumonia or sepsis, whereas AMB and flucytosine combination was more effective than fluconazole. This variation in drug activity can be explained by pharmacodynamic and pharmacokinetic properties of mono- or double-administration of therapeutic agents, as mentioned earlier.[21,32]
The International Society for Peritoneal Dialysis guidelines recommend administration of AMB combined with flucytosine for initial therapy of fungal peritonitis. More than 90% of AMB binds to protein after intravenous administration resulting in poor distribution in the intraperitoneal space. AMB causes severe peritoneal irritation and abdominal pain after intraperitoneal administration. In this negative situation, fluconazole alone or in combination with flucytosine has been preferred in some centers. Antifungal therapy should be subsequently continued by a suitable agent, after the specific fungal etiology and susceptibility pattern were identified.
Since azoles and polyenes act on the same target on the fungal cell membrane structure, considerable concern has arisen regarding the use of these antifungals in combination. Animal models of candidal infection have demonstrated variable results for survival and tissue burden and this conflicts with the findings of indifference or even antagonism. AMB application followed by azole exposure seemed disadvantageous in vitro and in animal models.[37,38] This is not usually observed in the clinical setting; fluconazole and AMB were used concurrently for the management of candidemia in adult nonneutropenic patients in a large clinical trial. Favorable results, not antagonism, were obtained as this combination provided faster microbiological sterilization.
Echinocandins are highly active and fungicidal against most Candida spp., therefore combinations of these antifungals with azoles or AMB have not been particularly impressive in vitro. No antagonistic interactions were observed between caspofungin and AMB in an experimental animal model infected with azole-resistant Candida albicans; this combination tended to result in favorable interactions in vivo and in vitro.
The superiority of combination therapy with liposomal AMB (L-AMB) and caspofungin to monotherapy with either agent was investigated in an animal study in Turkey. No significant difference was reported in terms of survival rates between monotherapy and combination groups, whereas reduction in tissue burden was prominent in the latter, warranting additional studies to examine the superiority of combination therapy.
Caspofungin has been used as combination therapy for persistent candidemia in a small group of neonates treated with AMB and/or fluconazole or flucytosine, and it was found to be an efficacious addition for the treatment of candidemia refractory to conventional antifungal therapy.
Terbinafine is a synthetic drug with activity on squalene epoxidase, an enzyme which has a role in ergosterol biosynthesis. Terbinafine is usually applied for treatment of superficial fungal infections. Combinations of terbinafine and azoles have been reported to show synergy (Table 2) in vitro against some Candida spp.. Clinical application of terbinafine and fluconazole coadministration was promising, as in resistant oropharyngeal candidiasis.[18,47] Echinocandin and terbinafine combination has been investigated in few studies, but beneficial comments for clinical practice remain to be determined.
Heat shock protein 90 (Hsp90) is a molecular chaperone that is present in the fungal cell wall and is upregulated in response to stress. The function of Hsp90 includes assisting in protein folding and cell signaling. Efungumab (Mycograb®, NeuTec Pharma, Manchester, UK) is a human recombinant monoclonal antibody targeting Hsp90, preventing a conformational change needed for fungal viability. Efungumab shows activity against Candida spp. when used alone and synergism when combined with fluconazole, caspofungin and AMB.[50,51] In a double-blind, randomized multicenter study, efungumab plus L-AMB produced significant clinical and culture-confirmed improvement in outcome for patients with invasive candidiasis. There are case report experiences for use of efungumab in children suffering invasive fungal sepsis. It was used as adjunctive therapy to systemic antifungals and was well tolerated,[53,54] but further studies are warranted before it can be recommended for routine use in children.
Cell surface proteins can be attached to the cell membrane via the glycolipid structure called glycosylphosphatidylinositol (GPI) anchor. E1210 is a novel first-in-class antifungal drug that blocks inositol acyltransferase in the GPI biosynthesis pathway. Thus GPI-anchored protein maturation is inhibited, resulting in defects in the fungal cell wall. This inhibitory effect is specific to fungi but not to human GPI biosynthesis enzymes. E1210 has potent broad-spectrum antifungal activity against major pathogenic fungi, such as Candida spp., Aspergillus spp. and other filamentous fungi. This agent may be a candidate for those fungal infections that are difficult to treat with currently available therapies.
Resistance to azoles among Candida spp., except Candida krusei, has been proposed to result from reduced accumulation of the drugs in fungal cells through active efflux. Ibuprofen is a well-known potent anti-inflammatory and analgesic drug. Other than these properties, ibuprofen shows synergy with fluconazole on Candida by blocking efflux pumps; hence, it restores resistance to azoles. This advantage opens new insights for the treatment of azole-resistant candidiasis.
Physicians dealing with immunodeficient hosts face the issue of optimal management for invasive aspergillosis (IA), yet debate about the appropriate salvage therapy in refractory cases to initial treatment of IA still remains.
Opportunistic mold infections are associated with a poor outcome, making combination therapy particularly appealing. Although a great number of in vitro and animal model investigations performed for effectiveness of antifungal combinations for IA are reported in the mycology literature, no prospective multicenter studies have been published evaluating concurrent use of these agents. The decision to initiate combinational antifungal therapy in practice is easier when the patient is more immunosuppressed and suffering from an ongoing uncontrolled fungal infection, in the hope of expanding antifungal spectrum. The use of antifungal combination is carried out in 31.3–47% of transplantation programs, and it is very popular as a second-line approach where it is used in up to 70.7–80% of cases.[59,60]
Currently, there are no clear-cut recommendations for efficacious antifungal combination in these difficult-to-treat mold infections. Data must be supported by adverse event profile and pharmacoeconomic impact of dual- or even triple-antifungal therapy.
Theoretical antagonism between the azoles and AMB has been a problem, making one hesitant to use them sequentially or in combination for the treatment of IA. In vitro experiences and animal studies with the combinations of polyene and azoles have been reviewed in detail.[15,18,21] The simultaneous use of fluconazole, itraconazole or ketoconazole with AMB has yielded variable, but mostly indifferent or even antagonistic effects. Pre-exposure to itraconazole resulted in poorer mycological efficacy and lower survival rate after administration of AMB in a murine model of aspergillosis. However, good efficacy has been observed in many case reports where polyene–azole combinations were given for mold infections.[63,64] The sequential therapy of the same drugs in a recent trial has revealed favorable outcomes as salvage therapy with polyenes. The combined use of polyenes with an azole drug should be avoided or used cautiously until more data have been collected in clinical trials.
Combinations of echinocandins with azoles or AMB in both in vitro and in animal experiments of IA have been reported to have a synergistic or indifferent effect. They are fungistatic against Aspergillus spp. with relatively minor side effects. A substantial positive effect with combination therapy for aspergillosis has been proven by use of caspofungin and voriconazole in several animal models.[67,68] This combination was associated with improved rates of sterilization of tissues compared with caspofungin alone, although survival was not better than with voriconazole monotherapy.
A prospective, multicenter study in solid-organ transplant recipients was conducted to compare the combination of caspofungin and voriconazole as initial therapy for IA with patients historically undergoing L-AMB treatment. Treatment success was 70% among those receiving the combination regimen versus 51% among those who received L-AMB, with a statistically insignificant end point (p = 0.08).
In the clinical setting, echinocandins have been combined with polyenes or azoles for more problematic mold infections, but most of the clinical trials reported are retrospective in design and with a limited number of cases. In a retrospective study, AMB formulations were used to treat confirmed IA in 47 patients suffering from a hematological malignancy/stem cell transplant. Treatment failure was observed, but combination therapy with voriconazole and caspofungin was found to be superior with respect to improved 3-month survival rate compared to monotherapy with voriconazole.
The efficacy and safety of a combination therapy including caspofungin and another antifungal (either AMB or an azole) in a small patient group (17 patients, age range: 3–80 years) with immunocompromised state was investigated to treat invasive fungal infections. Favorable response rate was 71% and survival rate at 3 months was 47%. Interestingly, hepatic failure was documented in up to half of the patients, drawing attention to close monitoring of liver function tests during combination treatment.
In another randomized, prospective open-labelled pilot study (Combistrat trial) hemato-oncologic patients were treated for probable or proven IA with L-AMB (3 mg/kg per day) plus either standard-dose caspofungin or high-dose L-AMB monotherapy (10 mg/kg per day). The combination therapy demonstrated a better outcome, as ten out of 15 (67%) patients receiving the combination therapy responded, versus four out of 15 (27%) receiving monotherapy, without a major concern about drug-related side effects. However, only 30 patients took part in this study.
The results of a retrospective analysis of 159 patients with hematological malignancies receiving salvage therapy for proven or probable IA indicated that combination therapy offers no advantage over L-AMB or echinocandins as single drugs (9% L-AMB, 28% echinocandins and 21% for combination therapy), but rather a negative impact related to toxicity and cost. This study is currently among the largest series reported.
The anxiety of toxicity related to combination therapy was also analyzed in patients with IFI in a large cohort with combinations of major antifungals, and serum creatinine, transaminase, alkaline phosphatase and bilirubin levels were monitored. Overall good response rate was 65%, a favorable toxicity profile was documented, and the combination of polyenes with triazoles was feasible, although in vitro data show critical antagonism of this combination.
In a recent article, a retrospective study was described in lung transplant patients who received a combination of voriconazole and caspofungin as primary therapy for IA. A median of 12.3 days was necessary for voriconazole to reach active blood levels, so that caspofungin as a combination agent provides coverage against Aspergillus infection and may overcome treatment failure due to subtherapeutic levels of voriconazole.
In a monocentric, retrospective study, the efficiency and safety of caspofungin plus posaconazole have been studied for salvage therapy in hematopoietic stem cell transplant recipients with IA refractory to primary treatment. An advantageous response was seen in 77% of patients; which encourages the use of this drug combination.
Posaconazole has been used in combination with other antifungal agents in severe Aspergillus infections, such as Aspergillus endocarditis, with some good results.
Combination treatment modalities for pediatric IFIs have been reported as case reports or retrospective studies.[79,80] A single-center study was conducted by Yilmaz et al. in 17 children (median age: 5.3 years; range: 0.5–17 years) with 19 IFI episodes. Most of the IFI was proven or probable (16 episodes) and treated first with L-AMB monotherapy for a median duration of 12 days (range: 3–69 days). Caspofungin was added to the therapy in 11 patients, and in the remaining six patients, a combination of caspofungin and voriconazole was started as salvage therapy. A favorable response was observed in 68.4% of 16 proven or probable IFI episodes with 12-week survival rate recorded as 75%. No serious side effects were observed among patients, suggesting that combination antifungal therapy can be considered safe and effective, even in children with high risk for IFI.
Anidulafungin is a novel echinocandin with activity against Candida and Aspergillus spp. This drug was associated with reduced tissue damage when combined with voriconazole, compared with either agent alone in vitro and in animal studies. This effect was more prominent when anidulafungin doses doubled. Anidulafungin and AMB combination for invasive aspergillosis in mice was shown not to be superior to single drug therapy in a recent study.
Anidulafungin was studied in neutropenic children with IFI and who were older than 2 years of age, and it was found to be effective and well tolerated. As mentioned, safety and effectiveness of anidulafungin in pediatric patients has not yet been approved.
Micafungin is also a recently marketed echinocandin and its in vitro combined use with voriconazole showed enhanced activity against Aspergillus fumigatus and Aspergillus terreus but not against Aspergillus flavus.[65,86] A combination of micafungin, caspofungin or voriconazole was tried together with L-AMB in a murine model with intracranial aspergillosis and survival rate was increased.
Studies investigating the utility of micafungin either alone or as combination for primary or salvage therapy were conducted in clinical trials. Both pediatric and adult populations were enrolled in such a multinational, prospective study, and no benefit of combination therapy including micafungin was shown over primary therapy of proven or probable IA.
Nearly a total of 100 pediatric and adult stem cell transplant recipients suffering from IA enrolled in a more recent, multicenter prospective open-label study. Most of the study group patients (92%) had received micafungin with another licensed antifungal agent, yielding 24% of success rate. Although these studies lack a great number of patients, they still encourage the use of these treatment modalities in difficult situations. On the other hand, side effects must be considered; micafungin was reported to cause abnormal hepatocyte proliferation in animal experiments, hence they should be used carefully.
These data point to echinocandins as good candidates – at least they are not harmful – for combination therapy with either an azole or polyenes. Combination of flucytosine and AMB has demonstrated disparate results against Aspergillus spp. in vitro, whereas rifampin and AMB have produced a synergistic effect when used together.[18,90] The addition of flucytosine to AMB was associated with improved survival in animal models of aspergillosis. Both flucytosine and rifampin penetrate to body tissues excellently, including the CNS, and they have been tried as an adjunct to AMB in the treatment of CNS aspergillosis. These applications are limited, and only have occasional success and cannot be projected to routine use for this indication.
The relatively poor in vitro activity against Aspergillus spp. of terbinafine makes this agent an unlikely candidate for combined therapy of IA; however, coadministration with AMB did not demonstrate antagonism, which would be expected for these two drugs acting on the same region in the mold cell membrane.
Nikkomycin Z, a chitin synthase inhibitor, has been evaluated with various combinations of other antifungals and demonstrated synergy with caspofungin and micafungin.
A very recent systematic review published last year has sought the evidence that addresses the role of combination antifungal therapy (mainly azoles with either an echinocandin or a polyene) in the treatment of invasive aspergillosis over 1071 patients who were enrolled in eight comparative studies (one randomized controlled trial and seven cohort studies). Cumulative evidence was found not to be strong enough to support routine combination therapy for primary IA and combination antifungal therapy to be conflicting and of moderate strength.
Other Rare Molds
Antifungal combination therapy, in particular, poses a place in rare invasive mold infection, as different genera in the same group may have variable in vitro susceptibility patterns, and some (e.g., Scedosporium spp.) possess intrinsic resistance to many of the conventional antifungals.
Mucormycosis, also named as zygomycosis, is a group of emerging mold infections, especially in transplant patients and in diabetics. Caspofungin does not show much effect in monotherapy; however, the in vitro effects of the combination of posaconazole with caspofungin have showed a synergistic interaction. There are adult case reports that describe successful outcomes with combinations of L-AMB with either caspofungin or posaconazole, where single-agent therapy has failed.[97,98] Posaconazole is occasionally used in children, usually as a salvage monotherapy or in combination with other antifungals for IFI and only minor adverse effects were observed with considerable response.
Another review mentions improved outcomes with AMB and caspofungin combination for rhinocerebral zygomycosis. The survival of Mucorales and causing invasive disease require host iron storage. Patients with hemochromatosis and also those receiving iron chelator deferoxamine are predisposed to mucormycosis. Unlike deferoxamine, deferasirox, a newer iron chelator agent plus L-AMB therapy have been shown to improve survival in a diabetic murine model of mucormycosis. However, in a multicentered, randomized, placebo-controlled, double-blinded clinical trial using the same treatment regimen, adjunctive deferasirox, for mucormycosis was found to be unsuccessful with no benefit from iron chelation.
The efficacies of micafungin, AMB and voriconazole, alone and in double or triple combinations, were studied in a murine model of systemic infection by Scedosporium prolificans. Micafungin combined with voriconazole or AMB was demonstrated to be most effective in lessening tissue burden and prolonging survival, without adding any benefit over double combinations. Clinical experience of this mold infection is limited to case reports and no generalized recommendations are available. Of interest, hexadecylphospocholine (miltefosine), an antileishmanial and antitrypanosomial agent, together with terbinafine and voriconazole has been used for a complicated case with S. prolificans bone infection as salvage therapy, and disease progression was reversed.
Disseminated mold infections due to Fusarium spp. are increasingly recognized in immunoincompetent hosts. Arikan et al. evaluated the efficacy of caspofungin–AMB against Fusarium species and reported all forms of drug–drug interactions (synergy in 50% of the isolates, additivity in 17% and indifference in 33%). Combination of caspofungin/terbutaline and caspofungin/FK-506 was strongly synergistic in vitro against Fusarium spp. in a recent in vitro study. Voriconazole plus AMB has shown a synergistic effect in animal models, pointing to this combination having a role in the treatment of fusariosis.
There are no evidence-based guidelines for fusariosis in immunocompromised patients recommending combination therapy. In a retrospective study evaluating a 12-year period, 44 cases with fusariosis had been treated by delivering mostly AMB and a triazole, with a survival rate of only 6% for 12 weeks of therapy. A pediatric hematologic case was treated using AMB and caspofungin, then oral voriconazole, showing conflicting data on success of antifungals.
There are not enough evidence-based clinical researches to make guidelines for rare mold infections. A lot of experience and knowledge should be obtained in order to be successful to treat those infections effectively in the guidance of these guidelines. A summary of clinical trials in which at least two antifungal combinations were used for invasive fungal infections in children is shown in Table 4.
In summary, combination antifungal therapy may be considered appropriate for the treatment of Candida CNS infections (especially in neonates), treatment of fungal CNS infections not responding to voriconazole, incomplete response to or intolerance of initial therapy, initial therapy of selected cases of invasive pulmonary aspergillosis (e.g., disease in close proximity to major mediastinal blood vessels), or empiric therapy of disease presumed to be organisms that are known to have distinct fungal susceptibility profiles.
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