Use of liposomal amphotericin B in bone marrow transplant

Increasing number of transplants worldwide has resulted in an increase in the incidence of fungal infections. Prolonged neutropenia, immunosuppression and graft vs. host disease all result in high predisposition to fungal infections. The likelihood of developing a fungal infection increases with the severity and duration of neutropenia, which, in the case of cancer or chemotherapy for the treatment of hematological malignancies, can range from a few days to several weeks. Invasive fungal infections are difficult to diagnose and neutropenic patients with fever often receive empirical antifungal therapy. This provides a rationale for the prophylactic use of antifungal agents. The empirical use of liposomal amphotericin B has overcome some of the difficulties usually found in this setting. The majority of clinical efficacy data related to liposomal amphotericin B are derived from compassionate use studies and case series. The major advantage of these liposomal formulations of amphotericin B is a reduction in amphotercin toxicity. Use of liposomal amphotericin has been shown to be a cost-effective approach abroad and the same has been our experience also. Commercially ambisome and Fungisome are the only products that contain true liposomes. Unlike ambisome, which needs to be used in dose of 3 mg/kg/day Fungisome is effective in the dose of 1-3 mg/kg bodyweight. The Indian liposomal preparation has shown to be safe and effective used in over 150 transplant patients in our experience. We conclude that the liposomal amphotericin is better-tolerated and also gives,better responses in documented fungal infections.     

High rate of breakthrough invasive aspergillosis among patients receiving caspofungin for persistent fever and neutropenia

A number of agents are now available for empirical antifungal treatment (EAFT) of patients with persistent fever and neutropenia. We carried out a study of efficacy of antifungal drugs to prevent breakthrough invasive aspergillosis by reviewing the medical records of all consecutive patients who received EAFT from November 2005 to February 2006. Patients’ characteristics and the type, dose and duration of antifungal therapy were recorded. Breakthrough invasive fungal infections were documented according to the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) definition. Fifty-six episodes of persistent fever with neutropenia requiring EAFT were recorded among 49 patients. All patients received high-dose chemotherapy for acute myeloid leukaemia (51%), acute lymphoid leukaemia (12%), lymphoma (14%) or other haematologic conditions (22%). Fourteen (29%) and five (10%) patients were allogeneic and autologous haematopoietic stem cell transplant recipients, respectively. Caspofungin was prescribed initially in 40 episodes (71%), amphotericin B (AmB) desoxycholate and liposomal AmB being prescribed in six (10%) and ten (18%) episodes, respectively. Six patients were switched from liposomal AmB to caspofungin because of adverse events. The median duration of antifungal therapy was 9 days. During follow-up, six patients (12%) were diagnosed with invasive aspergillosis after a median of 8 days (range 3–16 days) of EAFT. Invasive aspergillosis breakthrough occurred in 6/46 (13%) caspofungin recipients and in 0/16 (0%) AmB recipients (OR 3.1, p 0.32). The observed high rate of invasive aspergillosis among caspofungin recipients requires further evaluation.     

Febrile neutropenia in haematological malignancies

Fever is the principle sign of infection in neutropenic patient and frequently may be the only evidence of infection. The pattern of fever in neutropenia is non-specific and not pathognomonic of any type of infections or non-infectious process and can be suppressed by the antipyretic effects of drugs such as corticosteroids. Neutropenia, resulting from cytotoxic chemotherapy is the most common risk factor for severe infections in hematological malignancies. The duration of neutropenia also contributes significantly to the risk of serious infections. This risk is significantly greater a lower neutrophil counts, such that 100% patients with ANC <100 cells/microl lasting 3 weeks or more develop documented infections. The prompt initiation of empirical antibiotics in febrile neutropenia has been the most important advance in the management of the immunocompromised host. The initial empirical antibiotic regimen started at presentation of the febrile episode frequently requires modifications especially in high-risk febrile neutropenia. Neutropenic patients who remain febrile despite 4-7 days of broad spectrum antibacterial therapy are at a high risk of invasive fungal infection. Empirical antifungal therapy with Amphotericin B in persistently febrile neutropenic patients and other high risk patients has shown to reduce the risk of invasive fungal infection by 50-80% and the risk of fungal infection related mortality by 23-45% in 1980's. The IDSA has recommended that amphotericin B at 0.5-0.7 mg/kg/day be administered till marrow recovery. This approach is limited however by the adverse effects caused by drug infusion (fever, chills, myalgias, nausea, hypotension and bronchospasm). Lipid formulations which improve the therapeutic ratio of the traditional formulation are available. The safety and efficacy of these formulations is well established. These formulations have comparable efficacy and are less nephrotoxic than conventional amphotericin B.A lipid formulation of amphotericin B is appropriate as initial empirical therapy or as definitive therapy for proven mycosis in high risk patients receiving concomitant nephrotoxic drugs (cyclosporine), those with pre-existing renal impairment and those with protracted neutropenia during which dose limiting toxicity may occur.     

Adverse effects of antifungal therapies in invasive fungal infections: review and meta-analysis

Amphotericin B is the main therapeutic agent for the treatment of invasive fungal infections; however, it is associated with significant toxicities that limit its use. Other systemic antifungal agents have been developed to improve tolerability while maintaining the efficacy profile of conventional amphotericin B. Fifty-four studies involving 9,228 patients were assessed for the frequency of adverse effects of the main systemic antifungal agents. While the results suggest that liposomal amphotericin B (L-AmB) is the least nephrotoxic of the lipid formulations (14.6%), that conventional amphotericin B (AmB) is the most nephrotoxic (33.2%), and that itraconazole is the most hepatotoxic (31.5%), the lack of standard definitions of antifungal-related adverse effects limits the validity of these results. Furthermore, heterogeneous patient pools and differing protocols make it difficult to draw direct comparisons between studies. With the advent of newer classes of systemic antifungal agents, future trials should conform to definitions that are universally applicable and clinically relevant to allow for such comparisons and to enable evidence-based decision-making.     

Fungal Infections in Patients with Solid Tumors Treated with High-Dose Chemotherapy and Autologous Peripheral Blood Stem Cell Transplantation

The incidence and risk factors for fungal infection were assessed in 291 patients who had solid tumors and were undergoing autologous peripheral blood stem cell transplantation. The first 162 patients received prophylactic itraconazole, and 129 patients received nystatin. Empiric amphotericin B was given at day 7 of febrile neutropenia. Fungal infections developed in 52 patients: 47 (16%) were superficial and 6 (2%) were systemic. Itraconazole prophylaxis and only a few days of febrile neutropenia were independently associated with a decrease in the incidence of superficial infections. Only two patients required empiric amphotericin B. Systemic antifungal prophylaxis does not seem to be justified for patients with solid tumors and autologous peripheral blood stem cell transplantation. Empiric amphotericin B may be safely started at day 7 of febrile neutropenia. Electronic Publication     

Breakthrough infection of Trichosporon asahii during posaconazole treatment in a patient with acute myeloid leukaemia

A neutropenic patient with acute myeloid leukaemia experienced a breakthrough infection of Trichosporon asahii during posaconazole treatment. After treatment was changed to a combination therapy with voriconazole and liposomal amphotericin B, the infection resolved. Posaconazole works effectively as an antifungal prophylaxis and salvage therapy in rare invasive fungal infections. This case however illustrates that breakthrough infections with T. asahii may occur during posaconazole treatment.     

Reduction of systemic fungal infections in patients with hematological malignancies,neutropenia, and prolonged fever by early amphotericin B therapy

Summary A rate on autopsy of up to 30% systemic fungal infections and difficulties in diagnosing systemic mycosis antemortem have led to the empiric use of amphotericin B in patients with hematological malignancies, prolonged fever, and neutropenia. Routine empiric antifungal treatment was initiated in our institution in 1982. Amphotericin B was given to granulocytopenic patients with hematological malignancies with (a) unremitting fever after 48–72 h of antibiotic treatment, (b) recurrent fever during antibiotic treatment, or (c) with newly detected pulmonary infiltrates, sinusitis, skin and retinal lesions suggestive of a fungal infection. With this approach the rate of systemic fungal infections decreased significantly from 10% (27 of 270 patients; 1973–1981) to 4% (6 of 153 patients; 1982–1986,P<0.02). The reduction of systemic fungal infections was most prominent in patients with acute myelogenous leukemia, where its proportion decreased from 16% (16 of 98 patients; 1973–1981) to 4% (2 of 50 patients; 1982–1986,P<0.023). Our data support the hypothesis that the incidence of systemic fungal infections in patients with hematological malignancies and especially in acute myelogenous leukemia can be reduced significantly by empirical treatment with amphotericin B.     

Adverse effects of antifungal therapies in invasive fungal infections: review and meta-analysis

Amphotericin B is the main therapeutic agent for the treatment of invasive fungal infections; however, it is associated with significant toxicities that limit its use. Other systemic antifungal agents have been developed to improve tolerability while maintaining the efficacy profile of conventional amphotericin B. Fifty-four studies involving 9,228 patients were assessed for the frequency of adverse effects of the main systemic antifungal agents. While the results suggest that liposomal amphotericin B is the least nephrotoxic of the lipid formulations (14.6%), that conventional amphotericin B is the most nephrotoxic (33.2%), and that itraconazole is the most hepatotoxic (31.5%), the lack of standard definitions of antifungal-related adverse effects limits the validity of these results. Furthermore, heterogeneous patient pools and differing protocols make it difficult to draw direct comparisons between studies. With the advent of newer classes of systemic antifungal agents, future trials should conform to definitions that are universally applicable and clinically relevant to allow for such comparisons and to enable evidence-based decision-making.The online version of the original article can be found at: Editor’s note: This is a corrected and republished version of the original article that appeared in the European Journal of Clinical Microbiology & Infectious Diseases [Eur J Clin Microbiol Infect Dis (2005) 24:119–130], in which multiple references were omitted or incorrectly numbered due to a technical error.     

Efficacies and clinical roles of new antifungal agents]

Micafungin, a new class of the antifungal agent "echinocandin" released in 2002, and voriconazole, a new triazole antifungal agent released in 2005 in Japan have in vitro activities against Aspergillus spp. Results of large-scale clinical trials in Europe and the United States showed voriconazole to have superior efficacy against invasive pulmonary aspergillosis in comparison with conventional amphotericin B, and caspofungin, a member of the echinocandins, was effective as an empirical antifungal therapy in patients with persistent fever and neutropenia. In this way, choices of therapeutic medicine for aspergillosis are increasing more and more, and it is expected that the method of treatment will change greatly in future. On the other hand, we need to establish a new standard therapy for aspergillosis to avoid the clinical disruption caused by the variety of pharmaceutical choice caused. In this report, we describe the role of new antifungal agents for non-fumigatus Aspergillus infections, and the breakthrough in counteracting fungal infection using these new drugs.     

Two cases of disseminated mucormycosis in patients following allogeneic bone marrow transplantation

We describe two cases of disseminated mucormycosis following allogeneic bone marrow transplantation (BMT). Both patients were suffering from chronic graft-ver-sus-host disease (GVHD) and treated with prolonged administration of corticosteroid. In both cases, the initial symptoms were high fever and left flank pain. Involved organs were the spleen, right kidney and the right lung in one case, and the spleen and the brain in the other. The diagnosis was confirmed by pathology after splenectomy. One patient, in whom the immunosuppressants could be discontinued, was treated with prolonged conventional and liposomal amphotericin B and 5-fluorocytosine. The other, in whom the immunosuppressants could not be discontinued due to extensive GVHD, was unresponsive to amphotericin B, and eventually died from the fungal infection. Although mucormycosis, especially the disseminated form thereof is infrequent, it should be considered in high-risk patients because early diagnosis and timely therapy combining antifungal drug or surgery and reduction of immunosuppression appear to improve the prognosis.     

Renal impairment and amphotericin B formulations in patients with invasive fungal infections

A systematic review was performed to examine renal function in patients with invasive fungal infections, comparing the nephrotoxicity caused by conventional amphotericin B deoxycholate (c-AmB) with that induced by the use of lipid-based amphotericin B formulations. The analysis considered all comparative studies published in the literature between January 1996 and May 2007. The outcome data reviewed herein focused on renal toxicity as measured by serum creatinine (S-Cr) and the doubling or the mean difference in S-Cr levels from baseline to the end of therapy or the need for dialysis. We found that AmB lipid complex (ABLC), liposomal AmB (L-AmB) and AmB colloidal dispersion (ABCD) were significantly less nephrotoxic than c-AmB in all reported studies. ABLC and L-AmB caused low and comparable nephrotoxicity in nine studies. In one randomized study, L-AmB was significantly less nephrotoxic than ABLC. No studies compared ABCD nephrotoxicity to the other lipid formulations. Based on our review we conclude that lipid formulations of amphotericin B are an important strategy to preserve renal function and improve survival in critically ill patients who require treatment for systemic fungal infections.     

Antifungal Agents for Secondary Prophylaxis Based on Response to Initial Antifungal Therapy in Allogeneic Hematopoietic Stem Cell Transplant Recipients with Prior Pulmonary Aspergillosis

We performed a prospective study to evaluate the efficacy and safety of secondary antifungal prophylaxis (SAP) for patients with a history of invasive pulmonary aspergillosis (IPA) in allogeneic hematopoietic stem cell transplantation (allo-HSCT). In this study, the prophylactic agents used were chosen based on treatment response to initial antifungal therapy. One hundred and thirty-six patients undergoing allo-HSCT with prior IPA were enrolled in this multicenter study. The agents of SAP included itraconazole in 24, voriconazole in 74, caspofungin in 32, and liposomal amphotericin B in 6. Eighty-eight patients had stable IPA and 48 had active IPA at the time of transplantation. The success rate of SAP was 91.2%. Twelve patients developed breakthrough invasive fungal disease (IFD), and none discontinued antifungal agents because drug-related adverse events. The incidence of breakthrough IFD was neither different among the different antifungal agents (P = .675) nor between patients with active and stable IPA (P = .080). The 1-year cumulative incidence of IFD and IPA relapse was 27.3% ± 4.5% and 24.7% ± 4.4%, respectively. Our data indicate that SAP with antifungal agents based on initial antifungal therapy has favorable efficacy and safety in allo-HSCT recipients with prior IPA. Active IPA might not increase the risk of breakthrough IFD after transplantation.     

Controversial points in the treatment of patients with haematologic malignancies complicated with systemic fungal infections]

Prophylaxis and treatments for fungal infections differ with the infection type. However, the eradication of risk factors for outbreak of fungal infections, and the usage of appropriate antifungal agents are universally important to prevent these infections. For infections due to intrinsic fungi such as Candida spp., risk factors such as changes in normal flora by aggressive and prolonged broad-spectrum antibiotics therapy should not be permitted to emerge. On the other hand, infections due to extrinsic fungi such as Cryptococcus neoformans and Aspergillus spp. can be prevented by eradication of the colonized fungi using antifungal prophylaxis and the use of air-cleaning machines to combat colonization of patients and contamination in the hospital environment. The most important risk factor of fungal infections in patients suffering from haematologic malignancies is leukopenia. In these cases, it is crucial to reduce the duration of neutropenia and enhance the anti-microbial function using granulocyte-macrophage-colony stimulating factor. When a patient is complicated with a fungal infection, appropriate antifungal agents must be used at appropriate dosages for the appropriate period. However, there are still very few satisfactory antifungals with minimal adverse effects and good potential efficacy for systemic fungal infections. Therefore, combination therapy with amphotericin B and azole antifungals is necessary for patients with severe fungal infections. In patients complicated with fungal infections, the underlying disease is often resistant to aggressive antifungal therapy. Control of this underlying disease is thus a most important therapeutic factor.     

Role of granulocyte colony-stimulating factor in the treatment of mucormycosis

Several problems in the management of life-threatening mucormycosis remain unresolved, necessitating new methods of management. Four patients with histopathologically proven rhinocerebral mucormycosis were treated with high cumulative doses of granulocyte colony-stimulating factor (G-CSF). All had multiple predisposing factors for mucormycosis, particularly leukemia and neutropenia. Two patients refractory to fluconazole therapy were treated with liposomal amphotericin B. The improvement in clinical manifestations was closely related to neutrophil recovery, and all patients were alive at the end of therapy. In addition to surgical debridement and antifungal therapy, G-CSF seems to have played a role in their survival.     

Fungal infections in immunocompromised patients]

The number of immunocompromised patients is increasing due to the intensive therapy being administered those with cancer, organ transplant, and HIV infection. Fungal infections are one of the important opportunistic infections in immunocompromised patients. Early diagnosis is difficult, and the prognosis of these patinas is usually poor. Several methods of diagnosis for fungal infections have been developed: detection of antigens of the infected fungi from the sera is useful for early diagnosis; polymerase chain reaction (PCR) technology may be the most valuable method for the diagnosis of fungal infection in immunocompromised patients, and antifungal agents are the drugs used to the fungal infections in those patients. However, there are only five drugs available to fungal infections in Japan. Although amphotericin B is the recommended first choice for treatment of invasive aspergillosis, its use for immunocompromised patients is limited because of its adverse effects. Novel antifungal agents (azoles, amphotericin B drug deliver system, and 1,3-beta-D-glucan synthetase inhibitors) have been developed and some of these compounds undergoing clinical trials.     

Use of Voriconazole to Successfully Treat Disseminated <Emphasis Type="Italic">Trichosporon asahii</Emphasis> Infection in a Patient with Acute Myeloid Leukaemia

Trichosporon spp. is an emerging fungal pathogen in immunocompromised hosts, and disseminated infection is often fatal in neutropenic patients. Reported here is a case of disseminated infection in a neutropenic patient with acute leukaemia. After failure of amphotericin B and fluconazole therapy, the course of infection dramatically improved with voriconazole treatment. A literature search revealed 69 additional cases of disseminated Trichosporon spp. infections in neutropenic patients, and these are also reviewed. Clinical symptoms that suggest infection include fever, disseminated papulopustular cutaneous lesions and pulmonary involvement. Despite treatment with antifungal agents (amphotericin B, fluconazole), 78% of patients died. Voriconazole may represent a promising therapy for this life-threatening infection. Electronic Publication     

Invasive fungal infections: evolving challenges for diagnosis and therapeutics

Invasive fungal infections (IFI) parallel the explosive increase in the immunocompromized patient population, and are characterized by diagnostic difficulties and extreme mortality. Candidemia in a tertiary referral hospital in the Middle East confirms the current epidemiologic shift in this common blood stream pathogen towards non-malignancy cases (38%) and antifungal prophylaxis failure (20%), high presentation sepsis scores and attributable mortality (32%). Invasive aspergillosis (IA) is also associated with high mortality. Use of non-invasive computerized tomographic (CT) radiologic scanning linked to early administration of high dose liposomal amphotericin B (LAB) is associated with a reduced mortality of 9.5% compared to historical experience of 28%.Life threatening invasive aspergillosis also occurs in patients who are less obviously immunocompromized. Investigations may reveal subtle immune deficits which could place the patient at some risk for an invasive mycosis. Antifungal treatment used in combination with progenitor cell growth factors and gamma-interferon has proved successful in such situations of progressive fungal disease unresponsive to antifungal therapy alone.Pharmacologic remodeling of existing compounds by lipidisation reduces both the toxicity denominator and the efficacy numerator of the therapeutic index when compared to the parent drug. A comparative dose study of liposomal amphotericin B in aspergillosis has demonstrated equi-efficacy, generated debate over the ability of the controlled clinical trial to be capable of assessing antifungal efficacy, and illustrated that recovery from an invasive fungal infection may require maximum tolerated doses and immunomanipulation.Several new antifungal strategies are under clinical investigation. These include reformulating existing antifungals, exploitation of the growing knowledge of virulence factors to synthesize antagonists, immune reconstitution and immunoprotection. An interim analysis of an ongoing placebo controlled study of recombinant interleukin-11 to assess its efficacy in reducing sepsis in leukemia patients through prevention of chemotherapy induced gut epithelial cell apoptosis, has demonstrated a difference in the two study arms in sepsis rates and preservation of gastrointestinal epithelial cell integrity.The unique and special challenges presented by the dynamic epidemiologics of invasive fungal infections are demanding and attracting considerable responses, in the fields of diagnosis and therapeutics. Current strategies need considerable improvement, yet ongoing collaborative efforts will have a positive impact on our understanding of the fungus-host interaction and ultimately our ability to offer better care for our patients with invasive mycoses.     

Successful treatment with liposomal amphotericin B in two patients with persisting fungemia

Two granulocytopenic patients in whom fungemia persisted despite therapy with deoxycholate amphotericin B were subsequently successfully treated by daily intravenous administration of amphotericin B entrapped in sonicated liposomes made of egg yolk lecithin, cholesterol and stearylamine in a molar ratio of 4:3:1. High serum concentrations of amphotericin B could be maintained in both patients during therapy with liposomal amphotericin B and were associated with high in vitro antifungal activity. Liposomal amphotericin B was tolerated much better than the deoxycholate preparation. These findings suggest that the liposomal amphotericin B preparation is superior in the treatment of fungemia in granulocytopenic patients, and that randomized trials are warranted.Research Associate, Fund for Medical Scientific Research, Belgium.     

Clinical utility of antifungal susceptibility testing in patients with fungal rhinosinusitis

PurposeTo determine the association between antifungal susceptibility test (AFST) results and in vivo therapeutic response in Indian patients with fungal rhinosinusitis.MethodsThe clinicoradiological, fungal culture, AFST, histopathology results and outcomes of 48 patients with fungal rhinosinusitis seen between 20132015 were analysed. Minimum inhibitory concentration (MIC) determination was performed for amphotericin B, itraconazole, voriconazole and posaconazole.ResultsForty patients had invasive and 8 had non-invasive fungal sinusitis. Rhizopus and Aspergillus species which comprised 46.9% each of isolates were mostly associated with acute invasive fungal rhinosinusitis and chronic granulomatous fungal rhinosinusitis respectively. All patients with non-invasive fungal rhinosinusitis had Aspergillus isolates.The Geometric Mean (GM) MIC for R. arrhizus of amphotericin B and posaconazole was 0.51 mcg/mL and 3.08 mcg/mL respectively and for A. flavus species for amphotericin B and voriconazole values were 1.41mcg/mL and 0.35 mcg/mL respectively.In patients with Aspergillus infections, while there was no association of MICs for azoles and outcome (p = 1), a strong association was noted between azole therapy and a good outcome (p = 0.003). In patients with Rhizopus infections, no association was found between MICs for amphotericin B and outcome (p = 1) and because of therapeutic complications, no association was found between amphotericin B therapy and outcome (p = 1).ConclusionNo significant association exists between in vitro (AFST) and in vivo responses despite low GM MICs for the drugs used in Aspergillus and Rhizopus infections. Therapeutic complications following conventional amphotericin B therapy confounds analysis. Clinical responses suggest that azoles are the drug of choice for Aspergillus infections.