Lipid Formulations Of Amphotericin Research Articles

Invasive Mold Infections in Pediatric Cancer Patients Reflect Heterogeneity in Etiology, Presentation, and Outcome: A 10-Year, Single-Institution, Retrospective Study.

There is scarcity of data regarding invasive mold infections (IMIs) in children with cancer. We retrospectively identified patients (18 years old or younger) with malignant disease who developed proven or probable IMIs (European Organization for Research on the Treatment of Cancer/Mycoses Study Group criteria) during a 10-year period (1998-2008). We reviewed their risk factors and clinical characteristics and assessed their crude mortality rates and treatment outcomes 12 weeks after IMI diagnosis. Forty-eight patients (30 males) were identified, 30 (63%) of whom had a proven IMI. The most prevalent mold were Aspergillus species (40%), followed by Mucorales (20%) and Fusarium species (11%). Acute leukemia was the most common underlying malignancy (39 patients, [81%]). Twenty-three (59%) of them had refractory leukemia. Neutropenia was present at the day of IMI diagnosis in 67% of the patients. Sixty-two percent of the patients received prior corticosteroids. The dominant site of infection was the lungs (79%), followed by skin (29%) and sinuses (10%). Seventy-one percent of patients had radiological findings suggestive of fungal pneumonia (either nodules or masses). The mainstay of antifungal therapy was a lipid formulation of amphotericin B. Antifungal therapy resulted in 54% response rate (33% complete) at 12 weeks. The crude 12-week mortality rate was 31%. Logistic regression analysis demonstrated that monocytopenia (P=.013), malnutrition (P=.012), and intensive care admission in the month prior to IMI diagnosis (P=.027) were risk factors for death within 12 weeks. Although Aspergillus spp. was the most common mold in our pediatric cancer population, the epidemiology of the IMIs was diverse. Adults and children share similar risk factors for and epidemiology of IMIs.

Formas clínicas y tratamiento de las infecciones causadas por otros hongos filamentosos

An increase in infections by filamentous fungi other than Aspergillus has been observed in the last few years. Clear fungi or hyalohyphomycetes, dematiaceous or dark fungi, agents of mucormycosis, and Pneumocystis jirovecii are generally emerging opportunistic fungi that produce disseminated infection in patients with severe immunosuppression. The clinical manifestations in this group of patients are often non-specific as their expression is modified by the disease itself or by the concomitant treatments, which difficult early diagnosis. This, together with the relatively limited therapeutic resources available, has led to invasive fungal infections by these filamentous fungi being associated with significant mortality (30-100%). Nowadays with the emergence of the new triazole drugs or lipid formulations of amphotericin B, often combined with other antifungal drugs, attempts are being made to change the dire prognosis of patients with these infections.

Is There Still a Place for Conventional Amphotericin B in the Treatment of Neonatal Fungal Infections?

Neonatal invasive fungal infections (IFIs) remain an increasing problem associated with high rates of morbidity and mortality, as well as late-onset neurodevelopmental implications. Invasive candidiasis remains the leading neonatal IFI. Candida albicans is the fungal species most often affecting this population, although a changing epidemiologic incidence to non-albicans Candida species is reported in some neonatal intensive care units. Many treatment recommendations are extrapolated from adult populations, emphasizing the need to establish the optimal antifungal agent, dosage, and duration of therapy in neonates. Historically, conventional amphotericin B has been considered an efficient and safe treatment approach for most neonatal IFIs. More recently, lipid formulations of amphotericin B have been studied, used alone or in combination with other antifungal agents such as azoles or echinocandins. The aim of this article is to review the published experience in the use of amphotericin B formulations to treat neonatal IFIs.

Epidemiological trends in invasive aspergillosis in France: the SAIF network (2005–2007)

A prospective (2005–2007) hospital-based multicentre surveillance of EORTC/MSG-proven or probable invasive aspergillosis (IA) cases whatever the underlying diseases was implemented in 12 French academic hospitals. Admissions per hospital and transplantation procedures were obtained. Cox regression models were used to determine risk factors associated with the 12-week overall mortality. With 424 case-patients included, the median incidence/hospital was 0.271/103 admissions (range 0.072–0.910) without significant alteration of incidence and seasonality over time. Among the 393 adults (62% men, 56 years (16–84 years)), 15% had proven IA, 78% haematological conditions, and 92.9% had lung involvement. Acute leukaemia (34.6%) and allogeneic stem cell transplantation (21.4%) were major host factors, together with chronic lymphoproliferative disorders (21.6%), which emerged as a new high-risk group. The other risk host factors consisted of solid organ transplantation (8.7%), solid tumours (4.3%), systemic inflammatory diseases (4.6%) and chronic respiratory diseases (2.3%). Serum galactomannan tests were more often positive (≥69%) for acute leukaemia and allogeneic stem cell transplantationthan for the others (<42%; p <10-3). When positive (n = 245), cultures mainly yielded Aspergillus fumigatus (79.7%). First-line antifungal therapy consisted of voriconazole, caspofungin, lipid formulations of amphotericin, or any combination therapy (52%, 14%, 8% and 19.9%, respectively). Twelve-week overall mortality was 44.8% (95% CI, 39.8–50.0); it was 41% when first-line therapy included voriconazole and 60% otherwise (p <0.001). Independent factors for 12-week mortality were older age, positivity for both culture and galactomannan and central nervous system or pleural involvement, while any strategy containing voriconazole was protective.

Amphotericin B Lipid Complex in the Management of Invasive Fungal Infections in Immunocompromised Patients

Invasive fungal infections are associated with a poor outcome and their incidence is rising. Amphotericin B has for a long time been the gold standard for treatment of these infections, but the conventional formulation is associated with a high incidence of adverse events. Lipid formulations of amphotericin, developed to overcome these drawbacks, are now routinely used in clinical practice for the treatment of invasive fungal infections in immunocompromised patients. Amphotericin B lipid complex (ABLC) is prepared from amphotericin complexed to two phospholipids, a process that confers a number of important pharmacodynamic and pharmacokinetic properties compared with conventional amphotericin B. The results of retrospective observational studies and the analysis of databases, including the large Collaborative Exchange of Antifungal Research (CLEAR) database, have shown ABLC to be associated with response rates of up to about 80% in patients with confirmed fungal infections and around 60% in those treated empirically. Intranasal administration of ABLC for prophylaxis of invasive fungal infection in immunocompromised patients is safe and appears to be a promising treatment strategy for the future. ABLC is associated with a substantially lower incidence of nephrotoxicity than conventional amphotericin. Infusion-related reactions also occur less frequently than with conventional amphotericin and can be managed using premedication protocols. When direct and indirect costs are measured, ABLC appears to be less expensive than conventional amphotericin. The number of approved antifungal agents that are effective treatments for invasive fungal infections is increasing. However, lipid formulations of amphotericin, such as ABLC, are effective and well tolerated and remain the standard of care in the treatment of invasive fungal infections. Treatment strategies such as intranasal administration for prophylaxis and combination therapy with newer agents are future directions for these agents.

Candida infections in non-neutropenic children after the neonatal period

There are a variety of diseases, from local mucous membrane infections to invasive systemic infections, that are caused by Candida species. As a causative agent, Candida albicans is the most common; however, the other Candida species can also cause the same clinical syndromes. Most invasive fungal infections in children occur in the hospital setting. Candidemia is a serious condition associated with high morbidity and mortality and increased healthcare costs in pediatric patients. Children at the highest risk are those with prolonged intensive care unit stays, reduced immune function, recent surgery, prior bacterial infection, prior use of antibiotics and/or corticosteroids and other immunosuppressive agents, as well as use of a central venous catheter, total parenteral nutrition, mechanical ventilation and dialysis. Positive blood culture is the gold standard of candidemia; it should not be accepted as contamination or colonization in children with an intravascular catheter. However, in oropharyngeal or vulvovaginal candidiasis, culture of lesions is rarely indicated unless the disease is recalcitrant or recurrent. Recovery of Candida from the sputum should usually be considered as colonization and should not be treated with antifungal therapy. Antigen and antibody detecting tests are evaluated in invasive Candida infections; however, there are no published results in children, and their roles in diagnosis are also unclear. For the therapy of invasive Candida infections in non-neutropenic patients, fluconazole or an echinocandin is usually recommended. Alternatively, amphotericin B deoxycholate or lipid formulations of amphotericin B can also be used. The recommended therapy of Candida meningitis is amphotericin B combined with flucytosine. The combination therapy for Candida infections is usually not indicated. Prophylaxis in non-neonatal, immunocompetent children is not recommended.

Successful Treatment of Brainstem Blastomycosis with Fluconazole

The lipid formulation of amphotericin B is the initial drug of choice for central nervous system blastomycosis, but it is costly and associated with significant toxicity. This case report details a patient with primary pulmonary blastomycosis with dissemination to the skin, one joint, and the brainstem that was successfully treated solely with high-dose fluconazole.

Mycoses invasives au cours du traitement des maladies malignes de l’enfant

Intensified chemotherapy and hematopoietic stem cell transplantation result in severe and prolonged granulocytopenia with an increased risk of invasive fungal infections. The major fungal species that cause serious infections in cancer patients are Candida species and Aspergillus species. The main features of Candida infection in this context are oropharyngeal candidiasis and Candida esophagitis, chronic disseminated candidiasis, also known as hepatosplenic candidiasis, and candidemia. Aspergillus can cause severe lung infection but also sinusal or CNS infection. Because invasive fungal infections are severe and often life-threatening, preventive and empirical managements have become standard practice. An increasing number of antifungal drugs is now available, notably lipid formulations of amphotericin B (liposomal amphotericin B), new azoles with broad spectrum of activity and echinocandin.

Amphotericin B use in children: conventional and lipid-based formulations

Invasive fungal infections (IFIs) are important causes of morbidity and mortality in immunocompromised children. The increased incidence and high mortality rates associated with IFIs has led to development of novel antifungal agents to expand the breadth and effectiveness of treatment options available to clinicians. Since its initial approval in 1958, conventional amphotericin B deoxycholate had been considered the standard in treatment for IFIs. However, because of the dose-limiting toxicity of conventional amphotericin B deoxycholate, lipid formulations of amphotericin have been developed to potentially improve outcomes and mitigate the adverse effects associated with antifungal therapy. While less frequently employed today as prophylaxis (given the expanded availability of safer alternatives), amphotericin B is still considered a treatment option in select cases of severe or life-threatening IFIs. This article reviews the clinical use of amphotericin B for the prevention and treatment of IFIs.

INVASIVE CANDIDIASIS IN NON-HEMATOLOGICAL PATIENTS.

Candida is one of the most frequent pathogens isolated in bloodstream infections, and is associated with significant morbidity and mortality. In addition to haematological patients, there are several other populations with a substantial risk of developing invasive candidiasis (IC). These include patients undergoing prolonged hospitalisation with the use of broad-spectrum antibiotics, those fitted with intravascular catheters, admitted to both adult and neonate intensive care units (ICU) or gastrointestinal surgery wards and subjects with solid tumours undergoing cytotoxic chemotherapy. As a general rule, every immunocompromised patient might be at risk of Candida infection, including, for example, diabetic patients.The epidemiology of species responsible for IC has been changing, both at local and worldwide level, shifting from C. albicans to non-albicans species, that can be intrinsically resistant to fluconazole (C. krusei and, to some extent, C. glabrata), difficult to eradicate because of biofilm production (C. parapsilosis) or than might acquire resistance to azole during therapy.Delaying the specific therapy has been shown to increase morbidity and mortality, but traditional microbiological diagnosis is poorly sensitive and slow. Thus, culture-based treatment may result in therapy started too late. In order to reduce the mortality in IC, several management strategies have been developed: prophylaxis, empirical and pre-emptive therapy. Compared to prophylaxis, the latter approaches allow to reduce the use of antifungals by targeting only patients at very high risk of IC. Non-invasive serological markers and scores based on clinical prediction rules such as the presence of risk factors or Candida colonisation, have been developed with the aim of allowing prompt initiation of treatment. Although the use of these diagnostic tools in pre-emptive strategies is promising, the performance and cost-effectiveness should be tested in large trials.Agents recommended for initial treatment of candidemia in severely ill patients include echinocandins and lipid formulations of amphotericin B, while stable patients without risk factors for azole-resistance might be treated with fluconazole.

Mucormycosis of the Head and Neck

Mucormycosis of the head and neck is the most common form of infection by the order Mucorales, accounting for up to half of all cases. About 70% of rhinocerebral cases develop in diabetic patients. Less often, rhinocerebral mucormycosis occurs in solid organ transplant recipients, those with prolonged neutropenia, and those on deferoxamine therapy. Recently, rhinocerebral disease has been increasingly recognized in patients undergoing hematopoietic stem cell transplantation. A growing number of cases have presented as breakthrough infection in patients receiving voriconazole. The mortality rate of rhinocerebral mucormycosis has remained at 30% to 70% despite aggressive therapy. Early initiation of treatment substantially improves outcome, underscoring the need to maintain a high index of suspicion and promptly biopsy potential lesions. Surgical excision of necrotic tissue is essential. Lipid formulations of amphotericin B have become the standard treatment for mucormycosis. Posaconazole is useful as salvage therapy, but cannot be recommended yet as primary therapy.

Candidemia in the Pediatric Intensive Care Unit: What’s Different from Candidemia in Adults?

Candida species bloodstream infections have been associated with high morbidity and mortality, especially in patients hospitalized in a pediatric intensive care unit (PICU). The incidence of such infections is rising because of malignancies, prolonged PICU stay, and the use of broad-spectrum antibiotics. Although Candida albicans remains the most frequently isolated species, non-albicans Candida species have shown an increased frequency. Treatment with fluconazole or an echinocandin should be considered in patients at high risk for candidemia or as initial treatment for non-neutropenic patients with candidemia, in addition to the removal of intravascular catheters. Treatment with a lipid formulation of amphotericin B or caspofungin is suggested for neutropenic patients. Early diagnosis, prompt therapy, and prevention are the cornerstones of controlling infection and improving outcome. Although there are some differences between children and adults with candidemia, especially in antifungal drug therapy and outcome, in general the incidence, risk factors, species variation, diagnostic methods, and management are similar.

Antifungal prophylaxis and therapy in patients with hematological malignancies and hematopoietic stem cell transplant recipients

Patients with acute leukemia and hematopoietic stem cell transplant recipients are at risk of a spectrum of invasive fungal diseases corresponding to the type and intensity of immunosuppression. The development of newer antifungal agents has broadened therapeutic options. In the 1990s, lipid formulations of amphotericin B became widely used as safer alternatives to amphotericin B deoxycholate. In addition, fluconazole was shown to be beneficial as a yeast-active prophylaxis in hematopoietic stem cell transplant recipients. In the past decade, the antifungal armamentarium was further enhanced with the availability of extended-spectrum azoles and echinocandins. The development of effective broad-spectrum antifungal agents has led to their use as prophylaxis rather than delaying treatment until clinical signs of infection manifest. Antigen-based and PCR-based diagnostic adjuncts facilitate earlier detection of invasive fungal diseases compared with conventional culture, and have been incorporated into strategies in which initiation or modification of an antifungal regimen is targeted to patients with the highest likelihood of having fungal disease. Here, we review the pharmacological data and major clinical trials that guide the use of antifungals, as well as areas of uncertainty and future perspectives.

The value of amphotericin B in the treatment of invasive fungal infections

Over the last 20 years, there has been an increase in the total number of invasive fungal infections (IFIs) and in infections caused by rare and emerging pathogens. This is due in part to the growing population of immunocompromised patients at risk of developing fungal infections. Three classes of antifungal agents are widely used for the treatment of systemic fungal infections: polyenes, azoles, and echinocandins. Polyenes were the first antifungal agents developed and have a long-standing history in the treatment of IFIs. The use of conventional amphotericin B has been limited because of toxic side effects, which have been reduced by the lipid formulations of amphotericin B. Treatment options for invasive mycoses have expanded with the recent introduction of the second-generation triazoles (voriconazole and posaconazole) and the echinocandins (caspofungin, micafungin, anidulafungin). Despite the increased number of antifungal drugs, resistance issues present a problem in the treatment of IFIs. Although some fungal pathogens display innate resistance, others have developed resistance secondary to selective pressure. This article briefly reviews the changing epidemiology of fungal infections and associated risk factors, resistance issues with commonly administered antifungal agents, and treatment options for IFIs, with a focus on polyenes.

Cutaneous cryptococcosis in solid organ transplant recipients

Clinical manifestations, treatment, and outcomes of cutaneous cryptococcosis in solid organ transplant (SOT) recipients are not fully defined. In a prospective cohort comprising 146 SOT recipients with cryptococcosis, we describe the presentation, antifungal therapy, and outcome of cutaneous cryptococcal disease. Cutaneous cryptococcosis was documented in 26/146 (17.8%) of the patients and manifested as nodular/mass (34.8%), maculopapule (30.4%), ulcer/pustule/abscess (30.4%), and cellulitis (30.4%) with 65.2% of the skin lesions occurred in the lower extremities. Localized disease developed in 30.8% (8/26), and disseminated disease in 69.2% (18/26) with involvement of the central nervous system (88.9%, 16/18), lung (33.3%, 6/18), or fungemia (55.6%, 10/18). Fluconazole (37.5%) was employed most often for localized and lipid formulations of amphotericin B (61.1%) for disseminated disease. Overall mortality at 90 days was 15.4% (4/26) with 16.7% in disseminated and 12.5% in localized disease (P = 0.78). SOT recipients who died were more likely to have renal failure (75.0% vs. 13.6%, P = 0.028), longer time to onset of disease after transplantation (87.5 vs. 22.6 months, P = 0.023), and abnormal mental status (75% vs. 13.6%, P = 0.028) than those who survived. Cutaneous cryptococcosis represents disseminated disease in most SOT recipients and preferentially involves the extremities. Outcomes with appropriate management were comparable between SOT recipients with localized and disseminated cryptococcosis.

Recent Advances in the Treatment of Mucormycosis

In recent years, substantial advances have been achieved in the treatment of mucormycosis. It is now clear that early initiation of therapy results in substantially better outcomes, underscoring the need to maintain a high index of suspicion and aggressively biopsy potential lesions. Increasing data support the need for surgical excision of infected and/or necrosed tissue whenever feasible. Based on their superior safety and efficacy, lipid formulations of amphotericin B have become the standard treatment for mucormycosis. Posaconazole may be useful as salvage therapy, but cannot be recommended as primary therapy for mucormycosis based on available data. Pre-clinical and limited retrospective clinical data suggest that combination therapy with lipid formulations of amphotericin and an echinocandin improves survival during mucormycosis. A definitive trial is needed to confirm these results. The use of the iron chelator, deferasirox, as adjunctive therapy also improved outcomes in animal models of mucormycosis. However, its efficacy was not confirmed in a recent, phase 2 clinical trial. Additional study is required of the potential for abrogation of iron acquisition as adjunctive treatment of mucormycosis. Combination polyene-posaconazole therapy was of no benefit in pre-clinical studies. Adjunctive therapy with recombinant cytokines, hyperbaric oxygen, and/or granulocyte transfusions can be considered in selected patients. Large-scale, prospective, randomized clinical trials are needed to define optimal management strategies for mucormycosis.

Rhino-Orbital-Cerebral Zygomycosis in Solid Organ Transplant Recipients

Rhino-orbital-cerebral disease is a significant manifestation of zygomycosis in solid organ transplant (SOT) recipients. However, its characteristics and outcome are not well addressed. SOT recipients with zygomycosis as per the European Organization for Research and Treatment in Cancer and the Mycoses Study Group criteria in a cohort study at our centers published previously and those identified with a PubMed search from the 1950s to November 2009 were studied. Patients with mycosis involving the sinuses, orbits, or central nervous system (CNS) were included. Patients comprised a total of 90 SOT recipients with rhino-orbital-cerebral zygomycosis, including 13 in our cohort and 77 in the literature. CNS disease occurred in 57% (51 of 90). Overall mortality was 52.3% (46 of 88), and the mortality in patients with CNS disease was 73.5% (36 of 49). In logistic regression analysis, older age (odds ratio [OR] 1.12, 95% confidence interval [CI] 1.04-1.21, P=0.002) was associated with a higher mortality rate, whereas lipid formulations of amphotericin B compared with amphotericin B deoxycholate (OR 0.09, 95% CI 0.02-0.50, P=0.006) and surgery (OR 0.12, 95% CI 0.01-0.94, P=0.043) were independently associated with an improved survival even when controlled for CNS involvement and the era of diagnosis of disease. Rhino-orbital-cerebral zygomycosis, particularly CNS disease, is associated with substantial mortality rate in SOT recipients. Older age is a significant risk factor for mortality, whereas lipid formulations of amphotericin B and surgery improved outcomes.

Cryptococcal Meningitis: Current Approaches to Management in Patients With and Without AIDS

Cryptococcal meningitis is a life-threatening fungal infection of the central nervous system (CNS). Its management is characterized by the administration of initial combination antifungal therapy by following the principles of induction, consolidation, and maintenance therapy with aggressive management of elevated intracranial pressure (ICP). These tenets apply to patients with and without AIDS. Recent prospective trials on combination antifungal therapy, and the timing of the initiation of highly active antiretroviral therapy (HAART), suggest amphotericin B plus flucytosine and initiation of HAART are optimal therapy for management of patients with AIDS and cryptococcal meningitis. The paucity of prospective data on the management of cryptococcal meningitis in patients without AIDS is the most challenging aspect of formulating treatment guidelines, but the principles of induction, consolidation, and maintenance still apply. Combination antifungal therapy with a lipid formulation of amphotericin B plus flucytosine is generally indicated for this group, especially for those with a predisposition to renal dysfunction. Future research targeting this population may further inform recommendations.

Primary treatment of zygomycosis with liposomal amphotericin B: analysis of 28 cases

Lipid formulations of amphotericin B are increasingly used in lieu of deoxycholate amphotericin B for primary treatment of zygomycosis, but little is known about the efficacy of the former antifungal in treating this fungal disease. We therefore undertook an analysis of a case series of all patients with zygomycosis who received L-AMB for primary antifungal therapy in five major mid-Atlantic medical centers. Among the categories of variables studied were demographics, methods of diagnosis, microbiology, sites of infection, global responses, and survival. The median patient age was 44 years and 71% were male. Immunosuppressive hematological disorders (54%) were the most common underlying condition. Pulmonary disease constituted 50% of infections, sinus infection 29%, and cutaneous disease 18%. Members of the genus Rhizopus were the most common recovered agents. Success as defined by complete or partial positive response was noted in 32% of the cases. Concomitant surgery was performed in 46% of the cases, with similar response rates (31%). Overall survival was 39%. L-AMB was effective as primary therapy in only some patients in this cohort of highly immunocompromised individuals with invasive zygomycosis underscoring the importance of host response and the need for further advances for treatment of this lethal infection.

Management of Invasive Candidiasis in the Intensive Care Unit

Invasive candidiasis (IC) is an important infection in the intensive care unit (ICU) setting given its association with poor clinical outcomes. The epidemiology of IC is complex and, although incompletely elucidated, is characterized by considerable regional and temporal variability. Overall, there appears to be an increase in the incidence of IC and a change in distribution of the causative Candida spp. Of particular concern is an increase in the proportion of episodes caused by Candida glabrata, which is associated with reduced susceptibility to azole antifungal agents. The management of IC has been aided by the availability of several new antifungal agents. In particular, given their broad spectrum of activity and low toxicity, the use of echinocandins as first-line therapy is increasing, especially in settings where fluconazole-resistant Candida spp. are prevalent. Fluconazole remains a reliable agent where an azole-susceptible pathogen is confirmed or in settings where resistance is uncommon. Lipid formulations of amphotericin B are now generally reserved as second-line or salvage therapy. Voriconazole and posaconazole currently enjoy limited use for IC in the ICU setting. Although the poor outcomes associated with IC are, in part, related to the severity of underlying host factors, it is clear that optimization of treatment-related factors is also important. In particular, the speed of initiation of antifungal therapy and the achievement of pharmacodynamic parameters both influence outcomes. The most difficult challenge is early initiation of an effective antifungal drug, given the slow turnaround time and lack of sensitivity of conventional culture-based diagnostic techniques. New approaches, such as non-culture-based assays and/or clinical risk-predictive models are required to better target prophylactic, pre-emptive and empirical antifungal strategies.