Incidence of zygomycosis in transplant recipients

Recently, a remarkable increase in the incidence of zygomycosis has been reported from institutions in the USA and Europe. The use of voriconazole for the treatment of aspergillosis and, less frequently, the use of echinocandins as empirical treatment for invasive fungal infections are thought to be responsible for the increase. In addition, an increased incidence of this infection has been observed in transplant recipients, including both haematopoietic stem cell transplant (HSCT) and solid organ transplant (SOT) patients. There are no global surveys on the prevalence or incidence of zygomycosis, but data from individual institutions and countries show that zygomycosis is an emerging infection. The increased incidence of zygomycosis most probably reflects a greater frequency of predisposing factors, such as higher numbers of patients undergoing HSCT and immunosuppressive chemotherapy. In addition, the emergence of rare pathogens as a result of the rise in the use of antifungal therapy against common species can be postulated. Further, the availability of antifungal agents with activity profiles that are more specific for selected fungi increases the necessity of identifying pathogenic fungi; the frequency of Zygomycetes infections may have been underestimated until now because therapeutic decisions did not depend on the precise identification of pathogenic fungi.     

Cutaneous zygomycosis

The prevalence of cutaneous and soft tissue zygomycosis appears to have increased in recent years. We reviewed 78 case reports of cutaneous zygomycosis published from 2004 through 2008. Most patients with cutaneous zygomycosis have underlying conditions such as haematological malignancies, diabetes mellitus or solid organ transplantation, but a large proportion of them are immunocompetent. Trauma is the most common predisposing factor leading to zygomycosis in immunocompetent patients. If the patient is immunocompromised, the infection may disseminate. Cutaneous zygomycosis may be localized, may extend to deep underlying tissues, or may be disseminated. The most common clinical presentation is induration of the skin with surrounding erythema, rapidly progressing to necrosis. Histological examination and culture of soft tissue are important for the diagnosis of cutaneous zygomycosis. Treatment consists of surgical debridement, administration of antifungal agents (amphotericin B formulations and/or posaconazole) and, occasionally, hyperbaric oxygen. Mortality rates are approximately 30%.     

Disseminated Fusarium solani infection in patients undergoing hematopoietic stem cell transplantation]

A patient with a hematological malignancy is one example of a type of immunocompromised host, and critical opportunistic infections such as mycosis are not rare during medical treatment for such malignancy. Candidiasis and aspergillosis are typical mycoses and their importance has been recognized widely and great progress attained in their prevention and medical treatment. However, allogenic hematopoietic stem cell transplantation (allo-HSCT) to treat hematological malignancy has spread, and the increase in emerging mycoses such as Fusarium infection is reported. Fusarium spp. are common soil organisms and important plant pathogens, and have been conventionally known as a causative fungus of superficial mycosis in the dermatology and the ophthalmology domain. Reports of profound or disseminated Fusarium infection are found in immunocompromised hosts with such condition as a hematological malignancy or organ transplant, and have shown an upward tendency in recent years. The symptoms of disseminated Fusarium infection are shown in many cases with persistent fever refractory to antibiotics and pneumonia, and this is a highly fatal infection which merges fungemia with multiple organ injury such as that in the lung, liver, spleen, kidney, and the heart. Disseminated Fusarium infection has a high rate of isolation in blood cultures, and the rate of diagnosis while a patient is alive is high compared with aspergillosis, zygomycosis, etc. Despite the administration of anti-fungal drugs following allo-HSCT, two reported cases showing the symptoms of disseminated Fusarium infection finally died. Although definite diagnosis of these cases was made by blood cultures, no medical treatment effect with the anti-fungal drugs was determined. Since the existing antifungals are not expected to cure disseminated Fusarium infection certainly, an early diagnosis and the development of a new antifungal are desired to improve the medical treatment results.     

Invasive fungal infections in the paediatric and neonatal population: diagnostics and management issues

Invasive fungal infections in children appear to have increased over the past few decades. Especially neonates and children with primary and secondary immunodeficiencies are at risk. Candida and Aspergillus spp. are the most commonly isolated organisms. In addition, Malassezia may cause systemic infections in newborns and zygomycosis is important because of its rising incidence and high case fatality rate. Timely diagnosis and initiation of appropriate antifungal therapy is imperative for improving outcomes. However, traditional techniques are time-consuming and representative sample material, using invasive procedures, may be difficult to obtain in the paediatric setting. This review provides an overview of the advances in detection and rapid species identification, with a focus on issues relevant in these settings. Subsequently, the current antifungal treatment options for neonates and children are discussed in light of the antifungal spectrum of the available agents and the specific pharmacokinetic properties in different age groups. Although a multitude of newer antifungal compounds have become available within the last decade, further studies are necessary to clearly establish the role for each of these agents among neonates and children.     

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.     

In vitro activity of antifungals against Zygomycetes

To date, no reference standard for therapy for zygomycosis has been established because there are insufficient clinical data with which to make such a judgement. Knowledge of the species responsible for the infection and its antifungal susceptibility profile has become increasingly important in the management of patients. Amphotericin B is the most active drug against all the species involved, followed by posaconazole, whereas voriconazole has no activity. Echinocandins are completely inactive in vitro , but may be an interesting option when used in combination with other drugs.     

Invasive fungal infection in solid organ transplantation: toward evidence-based prophylaxis and preemptive treatment]

Although the opportunity to discuss infectious complications in solid organ transplantation is increasing in Japan as elsewhere, the length of clinical experience in extra-renal transplantation is still short and even experience in living donor organ transplant is very limited except for those involving the kidney or liver transplantation. Risk of invasive fungal infection in organ transplant recipients is highly dependent on the immunocompromised status accompanying end-stage organ failure before transplant operation and on the resultant history of infectious complications. These factors as well as surgical and postoperative should be incorporated in a systematic and dynamic manner to evaluate risk of invasive fungal infection. In addition to prophylactic management based on such risk evaluation, it is desirable that preemptive treatment be started on quantification of clinical symptoms, imaging diagnosis, screening culture, and serological indices. Emergence of newer and more potent antifungal agents with lower toxicity potentially changes the concept of antifungal treatment. On the other hand, early and impression-oriented preemptive treatment has tended to increase. It is still questionable whether the knowledge obtained from Western experience can be directly applied to solid organ transplant medicine in Japan. Extensive and detailed clinical experience is mandatory to pursue diagnosis, epidemiology, and risk factors in Japan and establish our criteria for prophylactic and preemptive use of antifungal agents.     

Current experience in treating invasive zygomycosis with posaconazole

The treatment of zygomycosis has two cornerstones, namely, surgery and antifungal drugs. In many patients, both need to be applied to achieve treatment success; without treatment, the mortality rate of zygomycosis approaches 100%. Because treatment options are limited, no well-designed randomized clinical trial has been conducted and data are predominantly derived from compassionate-use programmes or case reports. Amphotericin B (AmB) lipid complex (ABLC) was clinically evaluated for efficacy against zygomycosis in a single series and resulted in cure or improvement in 52% and in the stabilizing of disease in 20% of patients. Liposomal AmB (L-AmB) is frequently used, but no large series have yet been published. Posaconazole has demonstrated in vitro and in vivo activity against Zygomycetes. Two series demonstrated salvage treatment response rates of 60% and 79%, respectively. Antifungal combinations have not been evaluated thoroughly enough to warrant recommendations outside of clinical trials. Survival is usually associated with surgical debridement and improvement in underlying diseases. Currently, surgical debridement should be performed. Antifungal treatment should consist of either ABLC ≥5 mg/kg once per day or L-AmB ≥3 mg/kg once per day. When toxicity occurs or stable fungal disease is achieved, treatment can be switched to oral posaconazole 200 mg four times per day. If impaired kidney function is overt or expected on the grounds of, for example, uncontrolled diabetes, primary treatment of zygomycosis with posaconazole is an option.     

Immunomodulatory properties of antifungal agents on phagocytic cells

Phagocytic cells, particularly neutrophils and monocytes/macrophages, are the first line and the most effective form of innate host defence against pathogenic fungi. During antifungal therapy these phagocytic cells are also exposed to antifungal agents. In the phagocyte-fungus-antifungal agent interplay, drugs may directly interact with phagocytes through specific pattern recognition receptors, leading to altered antifungal activities. Antifungal agents, through modulation of fungal virulence, may initiate different immune response programs in the phagocytes, leading to antifungal synergism/antagonism or up-regulation of gene expression for a pro-inflammatory response. Additionally, indirect modulation of phagocyte behavior by pretreatment of neutrophils, monocytes, and macrophages with cytokines and exposure to antifungal agents have shown promising findings for combined drug-cytokine therapy that may improve treatment of life-threatening fungal diseases. In this review, we discuss the main in vitro and in vivo immunomodulatory effects of antifungal agents on phagocytes in response to pathogenic fungi, as well as we address underlying immunopharmacologic mechanisms and their potential impact on clinical outcome.     

Systemic fungal infections in immunocompromised patients

Opportunistic fungal infections are becoming more frequent complications during cancer therapy, after organ transplantation and in AIDS infections, especially after better control of bacterial infections in immunocompromised patients. Periods of prolonged neutropenia with neutrophil count less than 0.5 x 10(9)/L longer than 7 days, are the most important risk factors for the development of systemic fungal infections. Especially susceptible are the patients during treatment of acute leukemia, or after bone marrow transplantation. The most frequent causing agents of systemic fungal infections are Candida and Aspergillus species, than Cryptococcus neoformans and Mucor. Some other unusual species such Fusarium, Trichosporon, non-albicans Candida species of Candida are becoming more frequent, and is frequently resistant to conventional therapy. The difficulties in early and precise diagnosis of fungal infections, and the lack of adequate and efficient drugs are responsible for the high mortality of immunocompromised patients, even in potentially curable diseases. The recognition of risk factors, introduction of prophylactic measures, application of empirical antifungal therapy, are the procedures for the reduction of morbidity and mortality of invasive fungal infections. Fluconazole administration in prevention of systemic fungal infections, has become the standard approach, especially after bone marrow transplantation, while the oral itraconazole solution, has even more extended activity. Fluconazole appears successful also in the treatment of systemic Candidiasis. Conventional amphotericin-B is still the "gold standard" in the treatment of fungal infections. The new lipid formulations of amphotericin-B, intravenous itraconazole, has an identical efficacy, but are less toxic than conventional amphotericin-B. Several new promising agents are in the stage of clinical investigation like voriconazole, caspofungin, mycafungin and some other.     

Lipid formulations of amphotericin B as first-line treatment of zygomycosis

Zygomycosis is a difficult to treat and frequently fatal infection affecting immunocompromised and, rarely, immunocompetent patients. The early diagnosis and immediate initiation of treatment with an antifungal agent in combination with surgical intervention has proved critical for the favourable outcome of the disease. Few antifungal agents are available for treatment. Amphotericin B (AmB) deoxycholate has been the drug of choice for many years and is usually given at high daily doses which can result in renal toxicity. Currently, lipid formulations of AmB (liposomal AmB (L-AmB), AmB lipid complex (ABLC), AmB colloidal dispersion (ABCD)), mainly L-AmB, rather than conventional AmB have become the standard therapy. The rationale behind the use of lipid formulations is that they decrease the nephrotoxicity associated with longterm AmB use. Although there is a developing consensus that high doses of lipid formulations of AmB should be the antifungal therapy of choice for all patients with zygomycosis, until now there have been no data available with which to define the appropriate dose. The duration of therapy remains an unresolved issue, regarding both lipid formulations of AmB as well as sequential or combination treatments consisting of lipid formulations of AmB with posaconazole, a drug which has now emerged as a new therapeutic option.     

Immunomodulatory Properties of Antifungal Agents on Phagocytic Cells

Phagocytic cells, particularly neutrophils and monocytes/macrophages, are the first line and the most effective form of innate host defence against pathogenic fungi. During antifungal therapy these phagocytic cells are also exposed to antifungal agents. In the phagocyte-fungus-antifungal agent interplay, drugs may directly interact with phagocytes through specific pattern recognition receptors, leading to altered antifungal activities. Antifungal agents, through modulation of fungal virulence, may initiate different immune response programs in the phagocytes, leading to antifungal synergism/antagonism or up-regulation of gene expression for a pro-inflammatory response. Additionally, indirect modulation of phagocyte behavior by pretreatment of neutrophils, monocytes, and macrophages with cytokines and exposure to antifungal agents have shown promising findings for combined drug-cytokine therapy that may improve treatment of life-threatening fungal diseases. In this review, we discuss the main in vitro and in vivo immunomodulatory effects of antifungal agents on phagocytes in response to pathogenic fungi, as well as we address underlying immunopharmacologic mechanisms and their potential impact on clinical outcome.     

Prevalence and clinical features of Clostridium difficile-associated diarrhea in a tertiary hospital in northern Taiwan.

BACKGROUND AND PURPOSE: Although the clinical manifestations of and risk factors for Clostridium difficile-associated diarrhea (CDAD) have been extensively investigated in western populations, data from Taiwanese patients are comparatively limited. This study investigated the incidence density of CDAD in Taiwanese patients and also the risk factors and clinical manifestations of CDAD. METHODS: From September 21, 2003 to December 21, 2003, patients hospitalized in 2 infection wards and 6 medical intensive care units at National Taiwan University Hospital who were older than 20 years, had a history of antibiotic usage within the prior 6 weeks, and developed diarrhea without another identified etiology were classified as having antibiotic-associated diarrhea (AAD), and were enrolled for further study. The diagnosis of CDAD was established when toxin A of C. difficile was detected in stool. RESULTS: The incidence density of AAD was 1/100 person-days of antibiotics usage. CDAD accounted for 12.5% of AAD. Fever and abdominal discomfort developed in only less than half of CDAD patients. Pus cell in the stool sample was found in 100 percent of patients with CDAD. Univariate analysis revealed that presence of malignancy and treatment with antifungal agents within the previous 6 weeks were risk factors for CDAD development. In multivariate analysis, use of antifungal agents was the only independent risk factor for CDAD. CONCLUSION: The incidence density of CDAD in this study of Taiwanese patients with AAD was 12.5%. Prior usage of antifungal agents was the only independent factor associated with subsequent CDAD development in patients with AAD.     

Increase in aspergillosis and severe mycotic infection in patients with leukemia and MDS: comparison of the data from the Annual of the Pathological Autopsy Cases in Japan in 1989, 1993 and 1997

To study the relationship between the changes in visceral mycoses rates and recently advanced medical care in hematological settings, data on visceral mycosis cases with leukemia and myelodysplastic syndrome (MDS) that had been reported in the Annual of the Pathological Autopsy Cases in Japan in 1989, 1993 and 1997 were analyzed. The frequency rate of visceral mycoses with leukemia and MDS was 27.9% (435/1557) in 1989, 23.0% (319/1388) in 1993 and 22.3% (246/1105) in 1997. In comparing the rate of mycoses in recipients of organ or bone marrow transplantation with that of non-recipients, that of recipients was approximately 10% higher. The predominant causative agents were Candida and Aspergillus, at approximately the same rate as in 1989. The rate of candidosis decreased to one-half that of aspergillosis by 1993. Furthermore, severe mycotic infections clearly increased from 58.9% in 1989 to 75.6% in 1997. Among a total of 1000 cases with mycotic infection in those 3 years, acute lymphatic leukemia and acute myeloid leukemia were the major diseases (40.6% and 34.8%, respectively), followed by MDS (26.1%). The reasons for increased rates of aspergillosis and of severe mycotic infection can be surmised to be: (i) candidosis had become controllable by prophylaxis and by empiric therapy for mycoses with effective antifungal drugs; (ii) the marketed antifungal drugs were not sufficiently effective against severe infections or Aspergillus infections; and (iii) the number of patients surviving in an immunocompromised state had increased due to developments in chemotherapy and progress in medical care.     

Changing epidemiology of an emerging infection: zygomycosis

Aspergillosis and candidosis remain the most prevalent opportunistic fungal infections in immunocompromised patients, but diseases caused by the Zygomycetes have become of increasing importance. Exposure to antimycotic drugs with no activity against zygomycetes may be a new risk factor and an explanation for the increasing incidence of zygomycosis. The latter infection occurs only rarely in immunocompetent hosts, but in recent years Apophysomyces elegans has been described in many subtropical countries as an emerging pathogen causing mostly cutaneous infections after traumatic inoculation.     

Primary cutaneous cryptococcosis in immunocompetent and immunocompromised hosts.

A case of primary cutaneous cryptococcal infection is presented and cases of primary cutaneous cryptococcosis in normal and immunocompromised hosts are reviewed. Cutaneous cryptococcosis can occur from local inoculation or dissemination from a distant site of infection. Risk factors associated with development of primary cutaneous cryptococcosis are those which affect cell-mediated immunity, such as corticosteroid usage, solid organ transplantation, sarcoidosis and immunosuppression. The cutaneous manifestations of cryptococcosis are protean and may mimic other cutaneous diseases. Patients with a diagnosis of cryptococcosis from a skin biopsy or culture should undergo evaluation to exclude disseminated disease and an evaluation of cell-mediated immunity. Although some patients do well without antifungal therapy, these patients cannot be discerned prospectively and therefore antifungal therapy appears warranted in all patients with localized disease. Choice of therapy depends on the extent of disease and immunocompetence of the host.     

IL-17相关信号通路分子先天免疫缺陷在慢性黏膜皮肤念珠菌病中的研究及免疫治疗进展

慢性皮肤黏膜念珠菌病(chronic mucocutaneous candidiasis,CMC)较为少见,其为一组临床综合征,其特点为慢性复发性、常规抗真菌治疗难以治愈的皮肤、甲及黏膜的念珠菌感染,主要病原菌为白念珠菌。CMC主要为原发性免疫缺陷性疾病,目前分为两大类,最常见的为CMCD(CMC disease,CMCD),念珠菌感染多局限在皮肤黏膜的表面,不合并系统性白念珠菌感染或其他临床症状;系统性CMC(syndromic chronic mucocutaneous candidiasis,SCMC),除存在CMCD的症状外,可同时伴有其他病原菌的感染或系统性的侵袭性真菌感染或伴有其他临床症状。目前认为无论何种类型的原发性CMC均与细胞因子IL-17相关的信号通路分子基因突变致免疫缺陷相关。信号通路某些分子缺陷导致了Th17的增殖分化受阻、IL-17或者IL-22细胞因子分泌减少,或者中和IL-17、IL-22抗体增多等,由此导致了机体对念珠菌或者其他病原菌的易感性增加。在CMC治疗方面,除了应用传统的抗真菌药物如唑类、多烯类及棘白菌素类药物治疗外,生物制剂或者靶基因治疗都提供了可能的新的治疗策略。本文综述了与IL-17信号通路分子先天性免疫缺陷与CMC的相关性研究,并综述了可能的治疗方法和新的治疗靶点。     

Cladophialophora bantiana: a rare cause of fungal brain abscess. Clinical aspects and new therapeutic options

Black molds or dematiaceous fungi are rare etiologic agents of intracerebral abscesses and such infections carry a high mortality of up to 70% despite combined surgical and antifungal therapy. While the growing use of immunosuppressive therapies and organ transplantation have caused an increase in the incidence of rare fungal cerebral infections, occurrence in immunocompetent hosts is also possible. We describe a 60-year-old female patient with a cerebral abscess caused by Cladophialophora bantiana. The case illustrates the clinical and radiological similarities between glioblastomas and brain abscesses and emphasizes the need to perform histological and microbiological studies prior to the initiation of any form of therapy. Long-term survival from cerebral black mold abscesses has been reported only when complete surgical resection was possible. The recommended antifungal treatment involves the use of amphotericin B combined with a triazole and, if possible, flucytosine. Highly-active new generation triazole antifungal compounds (voriconazole or posaconazole) are likely to offer improved survival rates for patients with rare mold infections. In particular, posaconazole could be a new therapeutic option given its better tolerance, lower toxicity and fewer drug-drug interactions. We discuss clinical, microbiological and practical pharmacological aspects and review current and evolving treatment options.     

肺癌合并肺部真菌感染的诊疗进展

随着肺癌发病率的增加,肺癌合并肺部真菌感染的病人在临床上已经越来越常见,因其临床表现缺乏特异性又合并原发疾病,针对这部分的病人在早期诊断、治疗上仍然存在一定的困难.本文将从常见致病真菌、影像学表现和常用抗真菌药物、抗真菌治疗的研究进展等方面讨论肺癌病人合并肺部真菌感染的诊断和治疗.     

Combination antifungal therapy against Candida species: the new frontier--are we there yet?

In the past decade, we have seen a significant increase in the incidence of invasive fungal infections. In addition, opportunistic fungal infections resistant to antifungal agents have become increasingly common and their frequency will more than likely continue to increase. The antifungal armamentarium for the treatment of serious fungal infections remains limited. A possible approach to overcoming antifungal drug resistance and high mortality rates seen in severe fungal infections is to combine two or three classes of antifungals, especially if the drugs have different mechanisms of action. The unique properties of newer antifungals now provide us with the opportunity to investigate antifungal combinations that may become the standard of care for serious fungal infections. Combinations of new agents along with more traditional antifungals have now been shown to possess some synergistic or at least additive activity against Candida in clinical trials. On the other hand, caution is still needed since other antifungal combinations have demonstrated antagonistic activity in vitro. Well-controlled clinical trials are needed to define the most efficacious antifungal regimen. Furthermore, these trials should also evaluate the side effect potential of combination regimens and the pharmacoeconomic impact these regimens may have. Thus, while much optimism exists for combination therapy, there is much yet to be done.