Use Of Combination Antifungal Therapy Research Articles

Changing scenario of superficial fungal infection: Emerging resistance, recurrence and remedy in Bangladesh

Superficial fungal infections (dermatophytes) affecting skin, nail and hair are the most common infective dermatosis seen in dermatology outpatient clinics. There is a rising prevalence of dermatophytosis, especially in tropical countries like Bangladesh, with a concomitant increase in the number of difficult to treat cases. The reason for this phenomenon is not yet clear, but may be related to inadequate treatment regimen or discontinuation of medication, difficulties in eliminating predisposing factors and sources of re-infection. The pathogenesis and severity of fungal infection depend on various immunological and nonimmunological factors. The rampant use of antifungal therapy in immunocompromised individuals marked the onset of antifungal drug resistance. Fungal resistance can be microbiological or clinical. Genetic alterations in the fungi cause microbiological resistance. Clinical resistance is due to host or drug related factors. All these factors may cause fungal resistance individually or in tandem. Appropriate drug dosing along with antifungal drug susceptibility testing, especially for the dermatophytes isolated from chronic, recurrent cases or those with atypical presentation should be encouraged. Other ways to avoid resistance is the use of combination antifungal therapy. Combination therapy offers advantages in increased synergistic action with enhanced spectrum activity. Finally, newer insights into molecular mechanisms of drug resistance will help in the development of appropriate antifungal therapy. Till then experience based treatment of dermatophytosis is more effective than the standard guideline.
 Bangladesh Crit Care J September 2020; 8(2): 108-111

Combination antifungal therapy for breakthrough invasive mould disease in patients with haematological malignancies: when management reasoning eclipses evidence-based medicine.

Timely diagnosis and treatment of invasive mould disease is challenging in severely immunocompromised patients, particularly for patients who develop breakthrough infections while on antifungal prophylaxis. Currently, there are no high-quality data on how to best diagnose and treat these infections. Many essential decisions affecting the management of breakthrough mould disease are made before a definitive diagnosis is established. In this scenario, sound management reasoning often favours the use of combination antifungal therapy, especially when antifungal resistance, suspicion of undetected sites of infection or pharmacokinetic/pharmacodynamic limitations at the site of infection are likely. In these scenarios, pre-emptive use of antifungal combination therapy with frequent re-evaluation with an aim of de-escalation could be justified for many high-risk patients.

Combination Therapy for Invasive Fungal Infections

The purpose of this review is to summarize and evaluate relevant literature on combination antifungal therapy for invasive fungal infections (IFIs). Cryptococcal meningitis has the largest body and highest quality in support of combination therapy with amphotericin B and flucytosine. More recent data in treatment of invasive aspergillosis suggest combination therapy with voriconazole and echinocandins may be effective in select patients. Quality studies are needed to define combination therapy in rare mold infections. Multiple strategies have been employed to optimize treatment of the growing incidence of IFIs. With exceptions as noted above, justification for the use of combination antifungal therapy is most often based on uncontrolled and/or underpowered studies, in vitro data, and case reports.

Combination Antifungal Therapy for Invasive Mold Infections Among Pediatric Patients with Hematological Malignancies: Data from A Real-Life Case-Series.

Background:Invasive mold infections in children with hematological malignancies are associated with high mortality rates. The use of combination antifungal therapy in cases with a severe clinical course is increasing, although information on the efficacy and safety of this approach is limited.Methods:We present a case series of 13 children affected by hemato-oncological disorders who received combination antifungal therapy for invasive mold infections at our center (Pediatric Hematology, San Gerardo Hospital, Monza, Italy) from 2011 to 2016, with the aim of describing their clinical characteristics, types of infections, treatment regimens, clinical outcomes, and treatment safety. Medical records were retrospectively reviewed in order to describe patients' characteristics.Results:Combination antifungal therapy included liposomal amphotericin associated with caspofungin (5/13, 38.4%), voriconazole (5/13, 38.4%), or posaconazole (3/13, 23.1%). The 12-week treatment response rate was 69.2% (6/13 patients showed complete response, 3/13 partial response). The crude mortality was 30.7% (4/13): half was related to invasive mold infections (2/13, 15.38%) and half to disease progression (2/13, 15.38%). Overall, treatment was well tolerated, and we did not observe any permanent discontinuation of antifungals due to related side effects.Conclusions:In our experience, combination antifungal therapy seems to be a safe option in immunocompromised children with invasive mold infections. Well-designed studies are needed to confirm the safety of this approach and to better understand its efficacy in the pediatric setting.

How We Approach Combination Antifungal Therapy for Invasive Aspergillosis and Mucormycosis in Transplant Recipients.

Invasive aspergillosis and mucormycosis are life-threatening infections in solid organ and hematopoietic cell transplant recipients. Despite medical advancements in the care of these patients and the availability of new mold-active drugs, the outcomes remain suboptimal. Therefore, there has been increased interest in the use of combination antifungal therapy, in hopes that leveraging the possible in vitro synergy of these agents will improve the prognosis of invasive mold disease. However, there has been a large disconnect between the results of experimental and clinical investigations, as clinical studies have not unequivocally demonstrated the superiority of combination therapy over monotherapy. This is particularly true for mucormycosis, where the rarity of the condition has made it nearly impossible to prospectively study novel therapeutic strategies. We review the current standard of antifungal therapy and the preclinical and clinical data addressing the merit of combination therapy, and we provide guidance to optimize the management of these mycoses.

Updated guidelines for the diagnosis and management of aspergillosis

New guidelines for the diagnosis and treatment of infections due to Aspergillus species were published in August of 2016 by the Infectious Diseases Society of America (IDSA) (1), replacing those previously published in 2008 (2). These guidelines incorporate new data published between January 2008 and December 2014. The document provides guidance on non-culture-based diagnosis of Aspergillus infections, discourages the use of combination anti-fungal therapy for primary management, and begins to define the place in therapy for isavuconazole, a new anti-fungal drug of the azole class approved by the U.S. Food and Drug Administration (FDA) in March 2015 to treat aspergillosis and mucormycosis.

Combination Antifungal Therapy: When, Where, and Why

Combination antifungal therapy in the treatment of invasive fungal infections remains a controversial topic despite its increasing use based off case reports and series. There remains a paucity of well-controlled clinical studies to address which combination, the timing, and the benefits to the underlying host without causing toxicity. The evidence for using amphotericin B with 5 flucytosine for cryptococcal infections to reduce mortality has been effectively proven but the inaccessibility to 5 flucytosine requires the utilization of less effective combinations in many countries. For invasive aspergillosis, a large controlled clinical study in hematologic malignancy patients showed a trend for combination of voriconazole and anidulafungin to reduce mortality, especially in a subgroup of patients with positive galactomannan results. Outside of these two indications, the use of combination antifungal therapy in other patients and those with rare mold infections has not been proven and outcomes are heavily influenced by host factors rather than the combinations of antifungal treatment selected.

Combination Antifungal Therapy Experience at an Academic Health System

Invasive fungal infections are becoming increasingly prevalent, particularly in the immunocompromised population. The development of new antifungal agents with novel mechanisms of action has sparked interest in combination antifungal therapies. This study seeks to characterize combination antifungal use at a large academic health system. We conducted a retrospective observational study of adult inpatients with the intent of characterizing combination systemic antifungal utilization between the dates of July 1, 2012 and June 30, 2013. Combination antifungal therapy was defined as administration of two or more target systemic antifungals (liposomal amphotericin B, fluconazole, voriconazole, posaconazole, micafungin or terbinafine) for five or more days. Twenty nine patients received combination antifungal therapy and 36 unique treatment courses were identified. Ten of the 29 patients (35%) were BMT patients. Pneumonia was the most common disease indication (20/29; 69%). Unknown was the most common organism indication overall (11/29; 38%) and within the BMT patient population (6/10; 60%). Among the 36 unique treatment courses the most common combination therapy by drug class was an azole and an echinocandin (53%; 19/36) followed by a polyene and an azole (31%; 11/36). A significant proportion of the study population both overall (35%) and among BMT patients (60%) received combination antifungal therapy with no identified infecting fungal organism. There is no data to support such a practice. However, in the setting of severe invasive fungal infections, particularly in immunocompromised hosts, using additional antifungal agents may seem less risk-prone than invasive diagnostics like tissue biopsy. These findings suggest that earlier diagnostic methods including tissue biopsy are warranted to avoid unnecessary use of combination antifungal therapy when no pathogen has been identified.

Zygomycosis over‐infection during voriconazole therapy for aspergillosis in a heart transplant patient, successfully treated with liposomal amphotericin and posaconazole

Aspergillosis and zygomycosis are life-threatening fungal infections in immunocompromised patients. We report a heart transplant recipient with an early pulmonary invasive aspergillosis successfully treated with association of voriconazole and caspofungin. Zygomycosis sinusitis, which was diagnosed while he still was on voriconazole therapy, was successfully treated with the use of combination antifungal therapy including liposomal amphotericin plus posaconazole and conservative surgical debridement.

Monocular Vision Loss and Headache in a 60-Year-Old Liver Transplant Patient

Monocular Vision Loss and Headache in a 60-Year-Old Liver Transplant Patient

COMBINATION Antifungal THERAPY for Proven and Probable Invasive Fungal INFECTION IN HIGHLY Immunocompromised Patients.

Abstract 4644 INTRODUCTIONDespite the advent of new antifungal agents, the prognosis of Invasive Fungal Infections (IFIs) in highly immunocompromised patients remains poor. The current Mycoses Study Group Infectious Diseases Society of America Guidelines do not recommend the use of combination antifungal therapy for the routine treatment of IFIs. However, the use of combination therapy has become very prevalent in treating seriously ill immunocompromised patients. The purpose of this study was to collect the clinical experience of 7 Spanish Haematology Departments in antifungal combination therapy. Thus, we retrospectively examined all antifungal combination therapies applied in patients diagnosed with proven or probable IFIs in our centers. The main goal was to determine efficacy, toxicity and mortality among combinations. PATIENTS AND METHODSWe identified 52 patients (26 males and 26 females) who received antifungal combination therapy for more than a week in our institutions between October 2007 and May 2009. The mean age was 40.7 years (range: 2-73). The diagnosis of IFI was established according to the EORTC/MSG criteria. 31 patients were treated for haematological malignancies with high-dose chemotherapy for remission induction and the others 21 were undergone stem cell transplantation -9 HLA-identical sibling, 11 unrelated SCT, 1 autologous; the stem cells source was cord blood in 9 patients and 6 of the 21 receptors received reduced intensity conditioning regimen-. Underlying diseases were: 21 AML, 17 ALL, 7 MDS, 4 NHL, 1 MM, 1 CLL and 1 Biphenotypic Acute Leukemia. RESULTS26 patients had a proven IFI -12 Invasive Lung Aspergillosis, 4 Candidemia (2 C. Krusei and 2 C. Tropicalis), 2 generalized Fusarium, 5 Mucormicosis (3 rinocerebral and 2 pulmonar), 1 generalized Scedosporium Apiospermun, 1 cerebral Cryptococcus and 1 generalized Geotrichum Capitatum- and 26 had a probable IFI (all Invasive Aspergillosis). All patients but 4 received antifungal prophylaxis, 9 with fluconazole, 18 with voriconazole, 15 with itraconazole, 2 with liposomal amphotericin B (AmB) and 2 with caspofungin. Antifungal combination therapy was: AmB + caspofungin in 17 patients; voriconazole + caspofungin in 15 patients; voriconazole + AmB in 15 patients; AmB + posaconazole in 4 patients and voriconazole + anidulafungin in 1 patient. Global mortality was 59.6% (31 patients) and mortality due to IFI was 32,6% (17 patients). The combination therapy was well tolerated and no patient had severe toxicity that leads to discontinue the antifungal treatment, although mild renal and liver toxicity were seen. 37 patients (71.1%) showed a favourable response (28 complete and 9 partial) while unfavourable response were seen in 15 patients (28.9%). When we analyzed the results among antifungal combinations, the response rate was: 82.4% in caspofungin + AmB group, 66.76% in voriconazole + caspofungin group and 60% in voriconazole + AmB group. In spite of the best response in caspofungin + AmB group there were no statistically significances compared with voriconazole + caspofungin (p=0,3, chi square test) and voriconazole + AmB ( p=0,16, chi-square test). In 83.6 % of patients response was accompanied with granulocytic recovery. CONCLUSIONSThe prognosis of antifungal monotherapy for IFIs remains poor. In practice, clinicians are increasingly using antifungal combination therapy in highly immunocompromised patients although appropriate clinical trials evaluating this treatment have not been performed. Our findings show that combination therapy is well tolerated and good results are obtained with highly rates response in patients with this therapy. Future studies should be performed comparing antifungal combined therapy versus monotherapy and among different antifungal combinations. Disclosures:No relevant conflicts of interest to declare.

Disseminated aspergillosis in an adolescent with acute lymphoblastic leukemia

Disseminated aspergillosis in immunocompromised patients has a mortality rate of almost 100%. Despite the development of new antifungal agents, the outcome of disseminated aspergillosis has only improved slightly, particular in patients with central nervous system (CNS) involvement. The use of combination antifungal therapy might improve the dismal outcome of disseminated aspergillosis. We describe a critically ill adolescent with acute lymphoblastic leukemia who was successfully treated with voriconazole and caspofungin for disseminated aspergillosis with involvement of the lung, brain and thyroid gland.

Combination antifungal therapy: what can and should we expect?

Invasive fungal infections are associated with significant morbidity and mortality among immunocompromised patients. Recent advances in antifungal development have afforded us more pharmacologic compounds to choose from when managing these fungal infections. The role of combination antifungal therapy has been well established for fungal infections such as cryptococcal meningitis. The availability of new antifungals, increased incidence of mould infections and high mortality among certain affected populations, such as hematopoietic stem cell transplant recipients, has stimulated interest in the clinical use of combination antifungal therapy. In this paper, we review supporting evidence for the use of combination antifungals in the treatment of cryptococcal meningitis, invasive candidiasis, invasive aspergillosis and zygomycosis. Several controlled clinical trials have demonstrated benefits of combination antifungal approaches for patients with cryptococcal meningitis and invasive candidiasis, but variable effects when using different agents in combination have been reported. Randomized prospective studies of combination antifungal therapy in mould infections are lacking but some series provide supportive evidence for this approach. We also describe limitations of the data and these study designs, including the fact that we still need randomized controlled multicenter studies of combination antifungal therapy for mould infections. Trials in this area should be performed with efficiency and economics in mind, and could potentially use surrogate markers as end points. Therefore, we suggest future investigations of combination antifungal therapy should include a randomized, comparative trial of primary therapy for invasive aspergillosis.

Is combination antifungal therapy for invasive aspergillosis a necessity in hematopoietic stem-cell transplant recipients?

The use of combination antifungal therapy in hematopoietic stem-cell transplantation patients is controversial and limited by a paucity of controlled data. The recent literature is reviewed and the relative arguments for and against combination antifungal therapy are outlined with summative recommendations to assist practitioners in decision-making. There is an abundance of in-vitro and murine in-vivo combination antifungal literature, whereas clinical data are less abundant and controlled. Of the published case series there is a suggested benefit to combination therapy over monotherapy, although there are limitations to the available literature. Other issues in the combination debate that are addressed include the following: improved response rates and a survival advantage have been demonstrated in recent monotherapy studies; response rates in most published combination therapy studies do not suggest large gains over monotherapy; the lack of sustained survival advantage to combination therapy studies; and finally the consideration of host defenses in treatment responses. Based on available data, combination therapy is not warranted at the initial diagnosis of invasive aspergillosis. Randomized, controlled trials with rigorous study design are needed.

Pulmonary fungal infections

Invasive fungal infections of the lung have historically been associated with an extremely high mortality. This review aims to disseminate the most recent advances in the diagnosis and management of fungal infections of the lung. The number and diversity of immunosuppressed populations are growing rapidly. Transplant immunosuppression is becoming more aggressive early in the posttransplant period, potentially increasing the risk of invasive fungal infections. The galactomannan antigen test and the beta-D-glucan test have emerged as methods of serially monitoring at-risk patients for invasive aspergillosis. Their utility has been established in some neutropenic populations but not in solid organ transplant recipients. In-vitro studies, animal studies, and retrospective human studies support the use of combination antifungal therapy for invasive aspergillosis. Unfortunately no randomized clinical trials exist. Invasive pulmonary aspergillosis will continue to be a major problem in immunocompromised patients in the future. Immense advances in the last 2-3 years are sure to improve outcome. Well-designed multicenter evaluations are still necessary, however, to optimize management as management options widen.

Toward more effective antifungal therapy: the prospects of combination therapy.

The availability of new antifungal agents with unique mechanisms of action and improved tolerability has widened the possibilities for the use of combination antifungal therapy for difficult-to-treat opportunistic mycoses. However, the use of this therapy is largely governed by empiricism, especially in patients with invasive mould infections, for whom there is a tremendous need to improve outcomes. Because of the difficulties associated with the design and conduct of clinical trials of combination antifungal therapy for opportunistic mycoses, the majority of the studies evaluating antifungal combinations are still performed in the laboratory or using animal models of infection. However, the methods used to assess combined antifungal effects in vitro and in animals are poorly standardized, and there is little evidence that data generated from these studies can be translated in treating human mycotic infections. Despite the empiricism of combination antifungal therapy, certain principles help guide the use and study of these regimens.