Isavuconazole and Liposomal Amphotericin B as Successful Combination Therapy of Refractory Invasive Candidiasis in a Liver Transplant Recipient: A Case Report and Literature Review

Invasive fungal infections in liver transplant recipients are associated with elevated morbidity and mortality and pose a challenge to the treating physicians. Despite of lacking clinical data, the use of antifungal combination therapy is often considered to improve response rates in an immunocompromised patient population. We herein report a case of refractory invasive candidiasis in a liver transplant recipient treated successfully with a combination of isavuconazole und high-dose liposomal amphotericin B. The antimycotic combination treatment was able to clear a bloodstream infection with C. glabrata and led to regression of bilomas among tolerable side effects. The use of the above-mentioned antifungal combination therapy in a liver transplant recipient has not been reported previously. This case highlights the efficacy and safety of antifungal combination therapy in immunocompromised patients with refractory invasive candidiasis.

     

The Current Role of Posaconazole in Managing Zygomycosis

Zygomycosis is an emerging fungal disease that is associated with considerable excess morbidity and mortality. Standard approaches to treatment include reversal of the underlying immunodeficiency or metabolic disorder, surgical interventions, and antifungal therapy with amphotericin B lipid complex or liposomal amphotericin B. Among the newer triazoles, posaconazole possesses activity in vitro and in experimental animal models of zygomycosis, and two observational case series have demonstrated promising clinical responses in the salvage setting. This article reviews the current body of preclinical and clinical data and assesses the present and potential future role of posaconazole in managing zygomycosis.     

Efficacy of interferon-gamma and amphotericin B for the treatment of systemic murine histoplasmosis

The number of cases of systemic histoplasmosis has increased substantially in recent years, and improved therapy is needed. We examined the efficacy of immunomodulation with interferon (IFN)-gamma alone or in combination with a suboptimal regimen of amphotericin B for the treatment of primary systemic murine histoplasmosis. In the first study, BALB/c mice were infected with Histoplasma capsulatum G217B and treated with 10(5) U of IFN given every other day either preinfection and postinfection or only postinfection, alone or in combination with amphotericin B. IFN alone given subcutaneously (s.c.) postinfection prolonged survival over untreated controls (P < 0.01), whereas intravenous (i.v.) administration was ineffective. All combination regimens and amphotericin B alone significantly prolonged survival (P < 0.0001). The combination regimens of amphotericin B and IFN i.v. (pre- and postinfection) or IFN s.c. (postinfection) reduced the fungal burden in the liver and spleen; the latter regimen had superior efficacy in the spleen (P < 0.05) to either amphotericin B or IFN alone. After infection with a low-challenge inoculum, IFN given s.c. (pre- and postinfection) alone caused a significant reduction in fungal burden in the spleen (P < 0.001). In an acutely lethal model, combination regimens of IFN s.c. or i.v. and amphotericin B again prolonged survival (P < 0.01-0.001), with amphotericin B plus IFN given s.c. (pre- and postinfection) superior to all regimens (P < 0.05-0.01). This regimen also showed enhanced efficacy in causing the reduction of fungal burden in the spleen (P < 0.05). These results indicate that IFN in combination with AmB shows enhanced efficacy in the treatment of systemic histoplasmosis and support the potential utility of IFN as an adjunctive therapy.     

Primary Cutaneous Mucormycosis Presenting as a Giant Plaque: Uncommon Presentation of a Rare Mycosis

Mucormycosis is an uncommon opportunistic fungal infection caused by Zygomycetes. It usually affects immunocompromised, diabetic and trauma patients with infected wounds. We report a case of disseminated infection secondary to facial cutaneous mucormycosis caused by Saksenaea vasiformis in a diabetic patient who had a farming accident causing him severe head injury. The patient was treated with a combination of surgical debridement and antifungal therapy with liposomal amphotericin B, but he had a slow and fatal outcome. In cases of tissue necrosis following trauma involving wound contact with soil (i.e., potential fungal contamination), testing for the presence of Zygomycetes fungi such as S. vasiformis in both immunocompetent and immunocompromised patients is crucial. The reason is that this infection usually has a rapid progression and may be fatal if appropriate treatment is not administered.     

两性霉素B联合伊曲康唑或卡泊芬净治疗恶性血液病并发侵袭性真菌感染

目的观察两性霉素B联合伊曲康唑或卡泊芬净治疗恶性血液病患者并发侵袭性真菌感染(IFI)的临床疗效及安全性。方法收集我院联合治疗患者9例,对其疗效及毒副反应进行分析研究。结果9例患者7例有效,1例无效,1例停药。低钾是最常见的副反应,其他副反应包括畏寒、发热及肝、肾功能受损。结论两性霉素B联合伊曲康唑或卡泊芬净治疗IFI,经济、有效,患者依从性较好。     

Evaluation of antifungal pharmacodynamic characteristics of AmBisome against Candida albicans

A liposomal formulation of Amphotericin B (AmBisome), with small unilamellar vesicles containing amphotericin B, shows characteristic pharmacokinetics as liposomes, and in consequence, has different pharmacological activity and toxicity from amphotericin B deoxycholate (Fungizone). In this study, we evaluated the antifungal pharmacodynamic characteristics of AmBisome against Candida albicans using the in vitro time-kill method and murine systemic infection model. A time-kill study indicated that the in vitro fungicidal activities of AmBisome and Fungizone against C. albicans ATCC 90029 increased with increasing drug concentration. For in vivo experiments, leucopenic mice were infected intravenously with the isolate 4 hr prior to the start of therapy. The infected mice were treated for 24 hr with twelve dosing regimens of AmBisome administered at 8-, 12-, 24-hr dosing intervals. Correlation analysis between the fungal burden in the kidney after 24 hr of therapy and each pharmacokinetic/pharmacodynamic parameter showed that the peak level/MIC ratio was the best predictive parameter of the in vivo outcome of AmBisome. These results suggest that AmBisome, as well as Fungizone, has concentration-dependent antifungal activity. Furthermore, since AmBisome can safely achieve higher concentrations in serum than Fungizone, AmBisome is thought to have superior potency to Fungizone against fungal infections.     

Cost-Effectiveness Analysis of Combination Therapies for Visceral Leishmaniasis in the Indian Subcontinent

Background

Visceral leishmaniasis is a systemic parasitic disease that is fatal unless treated. We assessed the cost and cost-effectiveness of alternative strategies for the treatment of visceral leishmaniasis in the Indian subcontinent. In particular we examined whether combination therapies are a cost-effective alternative compared to monotherapies.

Methods and Findings

We assessed the cost-effectiveness of all possible mono- and combination therapies for the treatment of visceral leishmaniasis in the Indian subcontinent (India, Nepal and Bangladesh) from a societal perspective using a decision analytical model based on a decision tree. Primary data collected in each country was combined with data from the literature and an expert poll (Delphi method). The cost per patient treated and average and incremental cost-effectiveness ratios expressed as cost per death averted were calculated. Extensive sensitivity analysis was done to evaluate the robustness of our estimations and conclusions. With a cost of US$92 per death averted, the combination miltefosine-paromomycin was the most cost-effective treatment strategy. The next best alternative was a combination of liposomal amphotericin B with paromomycin with an incremental cost-effectiveness of $652 per death averted. All other strategies were dominated with the exception of a single dose of 10mg per kg of liposomal amphotericin B. While strategies based on liposomal amphotericin B (AmBisome) were found to be the most effective, its current drug cost of US$20 per vial resulted in a higher average cost-effectiveness. Sensitivity analysis showed the conclusion to be robust to variations in the input parameters over their plausible range.

Conclusions

Combination treatments are a cost-effective alternative to current monotherapy for VL. Given their expected impact on the emergence of drug resistance, a switch to combination therapy should be considered once final results from clinical trials are available.     

Biofilm Formation and its Impact on Antifungal Therapy

Fungi can protect themselves from host defences and antifungal drugs by the production of an extracellular hydrophobic matrix. Candida biofilms exhibit resistance to antifungal agents from all classes including the azoles, echinocandins, amphotericin B complex, and flucytosine. Although demonstrated on polystyrene and bronchial epithelia cells, until today, only indirect evidence for A. fumigatus biofilms in patients is available. The antifungals with the most activity against biofilms are the liposomal formulation of amphotericin B and agents in the echinocandin drug class. Importantly, echinocandins show excellent anti-biofilm activity against C. albicans at therapeutic concentrations. However, other biofilms formed by moulds, including A. fumigatus, are relatively resistant to echinocandins. Multiple mechanisms contribute to the intrinsic and acquired antifungal resistance during the different stages of fungal biofilm development. During the growth phase of the early biofilm various factors account for biofilm resistance. Combinational and sequential antifungal therapy as well as combination with enhancers can improve the effect of a single drug. Further studies are warranted to develop new therapeutic strategies targeting fungal biofilm-specific resistance mechanisms.     

Anfotericina B liposomal: farmacología clínica,farmacocinética y farmacodinamia

Liposomal amphotericin B is a lipid formulation of the antifungal drug amphotericin B with some distinguishing characteristics in its pharmacological behavior that entail some clinical differences of great interest. The significant improvement in the systemic and renal tolerability is one of them. This fact is related to the great stability of the liposome, promoted by its negative charge, the presence of cholesterol and the remarkable thermo-stability of the remaining lipids that compose it. In this situation, amphotericin B seems to be released from the liposome not spontaneously but when the liposome binds to the ergosterol in the fungal cell membrane. For this reason, there is almost no free amphotericin B in plasma or tissues, although it seems that its availability is greater when there is fungal infection. As a consequence, when the pharmacokinetic behavior is studied, the concentration and availability of liposomal amphotericin B are very high, and its volume of distribution is reduced in comparison with the other formulations.     

In?vitro and in?vivo study on the effect of antifungal agents on hematopoietic cells in mice

Liposomal amphotericin B, voriconazole, and caspofungin are currently used for systemic and severe fungal infections. Patients with malignant diseases are treated with granulocyte-colony stimulating factor (G-CSF) for the recovery of granulocytes after chemotherapy or hematopoietic cell (HC) transplantation. Since they have a high incidence of fungal infections, they inevitably receive antifungal drugs for treatment and prophylaxis. Despite their proven less toxicity for various cell types comparatively with amphotericin B and the decrease in the number of leukocytes that has been reported as a possible complication in clinical studies, the effect of liposomal amphotericin B, voriconazole, and caspofungin on HCs has not been clarified. The present study aimed to examine the in vitro and in vivo effect of these three modern antifungals on HCs. Colony-forming unit (CFU) assays of murine bone marrow cells were performed in methylcellulose medium with or without cytokines and in the presence or absence of various concentrations of liposomal amphotericin B, voriconazole, and caspofungin. In the in vivo experiments, the absolute number of granulocytes was determined during leukocyte recovery in sublethally irradiated mice receiving each antifungal agent separately, with or without G-CSF. In vitro, all three antifungal drugs were nontoxic and, interestingly, they significantly increased the number of CFU-granulocyte-macrophage colonies in the presence of cytokines, at all concentrations tested. This was contrary to the concentration-dependent toxicity and the significant decrease caused by conventional amphotericin B. In vivo, the number of granulocytes was significantly higher with caspofungin plus G-CSF treatment, higher and to a lesser extent higher, but not statistically significantly, with voriconazole plus G-CSF and liposomal amphotericin B plus G-CSF treatments, respectively, as compared with G-CSF alone. These data indicate a potential synergistic effect of these antifungals with the cytokines, in vitro and in vivo, with subsequent positive effect on hematopoiesis.     

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.     

In vitro activity of a liposomal nystatin formulation (Nyotran) against Cryptococcus neoformans

The in vitro antifungal activity of a new liposomal nystatin formulation (NISTL, Nyotran, Aronex Ltd., EE.UU.) was evaluated by a microdilution method with RPMI based on the M27A document of the National Committee for Clinical Laboratory Standards (NCCLS) against 22 isolates of Cryptococcus neoformans. This antifungal activity was compared with those of other seven antifungal agents, such as nystatin (NIST), amphotericin B deoxycholate, liposomal amphotericin B, amphotericin B lipid complex, amphotericin B colloidal dispersion, fluconazole, and itraconazole. NISTL was more active in vitrothan NIST, showing MIC values 2-3 fold smaller in 90% of the isolates. The results obtained suggest that this new formulation would be very helpful for the treatment of cryptococcosis.     

Fluconazole Non-susceptible <Emphasis Type="Italic">Cryptococcus neoformans</Emphasis>, Relapsing/Refractory Cryptococcosis and Long-term Use of Liposomal Amphotericin B in an AIDS Patient

The treatment of cryptococcosis is hampered by inefficacy or intolerance to the recommended antifungal agents. A patient diagnosed with AIDS had multiple relapses of cryptococcal infection, which became refractory to antifungal agents during the course of therapy. During the follow-up, the patient developed renal toxicity due to amphotericin B use and non-susceptibility of isolated Cryptococcus neoformans to fluconazole was detected. Thereafter, antifungal treatment was performed exclusively with liposomal amphotericin B, reaching a cumulative dose of 19,180 mg over 46 months. The final relapse of cryptococcosis occurred during the maintenance phase with liposomal formulation in a once-weekly dose. Measurement of the minimum serum concentrations of amphotericin B, determined sequentially before and after this relapse, suggested the importance of monitoring drug levels when the liposomal formulation is used for a long period.     

Amphotericin B: How Much Is Enough?

The total curative dose of amphotericin B for any given fungal infection or specific patient is not precisely known. Prior to the availability of lipid formulations of amphotericin B (LFAB), dosing of amphotericin B was dictated by its associated toxicity. The unique pharmacokinetic features of each LFAB have led to differences in their recommended doses. Most published data have evaluated doses of 3–5 mg/kg/day, although niches exist for both higher and lower doses. Low-dose LFAB allows for intravenous broad-spectrum antifungal coverage without drug-drug interactions and with reduced toxicity. High-dose LFAB demonstrates increased fungal clearance in animal models, although this has not translated to improved clinical outcomes for most invasive fungal infections. Although available data do not demonstrate significant benefit associated with high-dose therapy, for liposomal amphotericin B, the data also demonstrate no significant harm. As such, the use of high-dose liposomal amphotericin B for salvage therapy may be a consideration.     

急性淋巴细胞白血病患者侵袭性头状地霉感染1例及文献回顾

目的:通过报道1例急性淋巴细胞白血病患者侵袭性头状地霉感染的临床资料,并结合文献探讨头状地霉感染的临床特点、有效的诊断及治疗方法。方法:报道国内首例急性淋巴细胞白血病患者化疗后骨髓抑制期感染头状地霉病例,并对该病的诊断及治疗等进行系统文献回顾。结果:该白血病患者经血培养证实为头状地霉感染,并累及肺脏、肝脏和皮肤,治疗过程中先后采用卡泊芬净、脂质体两性霉素B和脂质体两性霉素B联合伏立康唑等治疗,虽然脂质体两性霉素B联合伏立康唑治疗患者体温正常,临床症状稍有改善,但是患者在化疗后40天放弃治疗并死于心肺功能衰竭。结论:头状地霉感染的发病率低,临床症状不够典型,诊断困难,预后差。根据患者的临床表现,结合血培养、GM实验、G实验和CT扫描等检查,可有助于诊断。头状地霉感染尚无非常有效的治疗方式,采用脂质体两性霉素B或两性霉素B联合伏立康唑或其他新的抗真菌药物可能获得一定的疗效,早期诊断、早期联合治疗和患者早期脱离粒缺状态是治疗成功的关键。     

A Mucormycosis Case in a Cirrhotic Patient Successfully Treated with Posaconazole and Review of Published Literature

Mucormycosis is an invasive fungal infection associated with a high mortality rate, especially in immunocompromised hosts. Mucormycosis rarely occurs in cirrhotic patients. Here, we report a case of mucormycosis with underlying liver cirrhosis and diabetes mellitus. The patient suffered from maxillary sinusitis and osteomyelitis, and the infection was successfully treated with antifungal agents, surgical debridement, and hyperbaric oxygen therapy. The antifungal treatments used were liposomal amphotericin B, itraconazole, and posaconazole. Although our patient had liver cirrhosis (Child-Pugh classification B), no hepatic decompensation was developed during the treatment course of posaconazole. This is the first report of the safe and effective use of posaconazole for the treatment of mucormycosis in a cirrhotic patient.     

Physical biochemistry of a liposomal amphotericin B mixture used for patient treatment

There seems little doubt now that intravenous liposomal amphotericin B can be a useful treatment modality for the management of immunocompromised patients with suspected or proven disseminated fungal infections. Interestingly, the very significant reduction in toxicity reported when amphotericin B is part of a bilayer membrane is closely tied to the physical characteristics of the liposomes involved, although these are poorly understood at the molecular level. We record here an examination by spectroscopy and freeze-etch electron microscopy of unsonicated amphotericin B multilamellar vesicles prepared along the lines that we and others have followed for samples used in clinical trials and preclinical in vivo or in vitro studies. Our study has focussed on liposomes of 7:3 dimyristoylphosphatidylcholine/dimyristoylphosphatidylglycerol (DMPC/DMPG) bearing 0-25 mol% amphotericin B, since this lipid mixture has been the choice for the first clinical trials. Phase transition behaviour of these liposomes was examined by electron paramagnetic resonance (EPR) spectroscopy of a nitroxide spin label partitioning into the bilayers. The same experiments were then performed on similarly prepared liposomes of the disaturated species, dipalmitoylphosphatidylcholine (DPPC), and the diunsaturated species, dielaidoylphosphatidylcholine (DEPC). Partial phase diagrams were constructed for each of the lipid/drug mixtures. Melting curves and derived phase diagrams showed evidence that amphotericin B is relatively immiscible with the solid phase of bilayer membranes. The phase diagram for DEPC/amphotericin B was very similar to that of DPPC/amphotericin B, and both exhibited less extensive temperature ranges of phase separation than did the 7:3 DMPC/DMPG mixture with amphotericin B. Between 25 and 37 degrees C the measured fluidity of the 7:3 DMPC/DMPG liposomes was similar to that of the (unsaturated fatty acid) DEPC liposomes, and considerably higher than that seen for (saturated fatty acid) DPPC liposomes. Preparations of 7:3 DMPC/DMPG, DPPC, and DEPC containing 0-25 mol% amphotericin B were examined by freeze-etch electron microscopy at 35 and 22 degrees C (to cover the temperature range of the mammalian body core and periphery). The same liposome features were present in all three liposome types studied. The appearance of individual liposomes at x 100,000 magnification reflected their molecular characteristics, which were found to be significantly heterogeneous within each batch. The lipid/drug structures were bilayer in nature, although liposomes showing considerable disruption were common, particularly at the highest drug concentrations.(ABSTRACT TRUNCATED AT 400 WORDS)     

Therapeutic Activity of Liposomal Amphotericin B in Systemic Mycoses

Abstract

Several clinical trials are presently underway to study various liposomal formulations of antineoplastics and antimicrobial agents (1–3). Both liposomal amphotericin B (L-AmpB) and various liposome formulations have been used in the treatment of experimental systemic fungal infections (4–6) and leishmaniasis (7,8) in animals. In most reports, an enhanced therapeutic index was observed. A uniform reduction in the toxic effects usually attributed to AmpB was reported and, in some cases, an enhanced therapeutic efficacy was also attained. We recently reported on the use of L-AmpB in 46 patients with systemic fungal infections (9). of that number, 31 had leukemia, 2 had lymphoma, 11 had other diagnoses (5 had received intensive immunosuppressive therapy following a heart transplantation, 2 had multiple myeloma, and the rest had other malignancies); 2 patients had no underlying disease. Forty-one of these patients had been previously treated with conventional AmpB. the fungal diagnosis was candidiasis in 21 patients, aspergillosis in 19, agents of mucormycosis in 3, and other diagnoses in the rest.     

Pegylated liposomal doxorubicin in ovarian cancer

Pegylated liposomal doxorubicin is a formulation of doxorubicin in which the molecule itself is packaged in a liposome made of various lipids with an outer coating of polyethylene glycol. Liposomal technology is being used in increasing amounts in the therapy of a variety of cancers, including ovarian cancers. This article reviews the mechanistic actions of this formulation, the Phase II and Phase III data that helped define the role of pegylated liposomal doxorubicin in recurrent ovarian cancer, as well as a discussion of some of the side-effects and their management.     

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.