Changing epidemiology of rare mould infections: implications for therapy

There has been an increase in rare mould infections in recent decades. These infections have been reported primarily in severely immunocompromised patients. The emergence of these organisms is multifactorial and can be related to more intense immunosuppression, the prolonged survival of patients who have what were previously fatal diseases, and the selective pressure of broad spectrum antifungal agents used for prophylaxis or therapy. Among these rare mould infections, the Zygomycetes are the most commonly encountered, and in some institutions the increase in these organisms appears to be associated with the use of voriconazole. Aspergillus terreus, a species that is resistant to amphotericin B, and less frequently, A. ustus and A. lentulus, have been noted increasingly as causes of invasive aspergillosis in tertiary care centres in the US. Several species of Scedosporium with innate resistance to many antifungal agents have emerged as major causes of disseminated mould infections that are frequently very difficult to treat. Among patients who have haematological malignancies, are neutropenic or have received a haematopoietic stem cell transplant, infections due to Fusarium species respond poorly to many antifungal agents. Dematiaceous, or brown-black, fungi, most often associated with chronic localised infections, are now increasingly reported as a cause of disseminated infection in immunosuppressed hosts.Concomitant with the increased number of infections with these rare moulds, several new mould-active antifungal agents have been developed. The new expanded spectrum azole, voriconazole, has changed our approach to moulds such as S.apiospermum, Fusarium species and A. terreus that are amphotericin B resistant. Posaconazole, the most recently approved expanded spectrum azole, is the first drug in the azole class to show activity against the Zygomycetes and has proven extremely useful for step-down therapy after initial treatment with amphotericin B. It is not known whether posaconazole is effective as primary therapy for zygomycosis; the use of this agent for that purpose awaits clinical trials with the recently developed intravenous formulation of posaconazole.     

Management of systemic candidal infections in the intensive care unit.

Risk factors and treatment strategies for systemic candidal infections in the intensive care unit (ICU) are discussed. The past two decades have seen a dramatic increase in the frequency of infections caused by Candida species. Risk factors associated with candidemia include treatment with multiple antimicrobials for extended periods, presence of central venous catheters, total parenteral nutrition, colonization by Candida species, abdominal surgery, prolonged stay in the ICU, and compromised immune status. Since the 1960s, conventional amphotericin B has been the primary treatment option for fungal infections. Although effective, amphotericin B has extensive toxicity. Three lipid-based formulations of amphotericin B have been developed in an attempt to decrease nephrotoxicity and improve drug delivery. Practitioners have also been offered alternatives by the introduction of less toxic azole antifungals, such as ketoconazole, fluconazole, and itraconazole; however, their widespread use has resulted in other problems, such as the selection of resistant isolates. There is controversy concerning fluconazole's effectiveness. In the treatment of systemic candidal infections, especially in critically ill patients. Clinical trials do not support the prophylactic or empirical use of fluconazole in the ICU. Treating patients who have no microbiological evidence of infection provides no therapeutic benefit and shifts the fungal flora to noncandidal strains that are more resistant to fluconazole. Patients in ICUs are often susceptible to systemic candidal infection. Preemptive therapy with fluconazole may reduce mortality in high-risk patients. Fluconazole and amphotericin B appear equally effective in treating established systemic candidal infections.     

In vitro antifungal activity of posaconazole against various pathogenic fungi

The antifungal activity of posaconazole (SCH56592), a new triazole antifungal, against stock cultures and fresh clinical isolates of a wide range of pathogenic fungi was compared with that of itraconazole, fluconazole and amphotericin B. Posaconazole inhibited growth of all the fungal species tested except Fusarium spp. at 1 mg/l or lower concentrations, showing a broad-spectrum antifungal activity. The activities of posaconazole for all the fungal species far surpassed those of fluconazole and were even superior to those of itraconazole for Aspergillus spp. as well as for many other fungal species.     

Micafungin: a review of its use in adults for the treatment of invasive and oesophageal candidiasis, and as prophylaxis against Candida infections

Intravenous micafungin (Mycamine; Fungard), an echinocandin, inhibits the synthesis of 1,3-beta-D-glucan, an essential cell wall component in many fungi. It is approved in adults (focus of this review) and in neonates and paediatric patients (Pediatric Drugs [in press]) in the EU and elsewhere for the treatment of invasive candidiasis and oesophageal candidiasis, and as prophylactic treatment to prevent Candida infections in haematopoietic stem cell transplant (HSCT) recipients.Intravenous micafungin shows very good activity against clinically relevant isolates of Candida spp. Furthermore, the pharmacokinetic profile of micafungin permits once-daily treatment and means that it is associated with relatively few drug-drug interactions. However, like all of the echinocandins and all formulations of amphotericin B, micafungin must be given intravenously. In large, well designed clinical trials in adult patients (>or=16 years of age) with invasive candidiasis, intravenous micafungin was shown to be noninferior to intravenous caspofungin or liposomal amphotericin B. In similarly designed trials in adult patients with oesophageal candidiasis, intravenous micafungin was shown to be noninferior to fluconazole or caspofungin treatment. As prophylactic treatment in adult and paediatric patients who had undergone HSCT, micafungin was superior to fluconazole therapy in a large, well designed trial. Micafungin was generally well tolerated by participants in these clinical trials. Furthermore, it was as well tolerated as caspofungin and fluconazole, and better tolerated than liposomal amphotericin B. The position of micafungin relative to newer antifungal therapies, such as anidulafungin, voriconazole and posaconazole, remains to be fully determined. Thus, micafungin is an emerging option for the treatment of adult patients with invasive or oesophageal candidiasis, and as prophylaxis against Candida infections in HSCT recipients.     

symbol: see text]Caspofungin and [symbol: see text]voriconazole for fungal infections

Systemic fungal infections are difficult to treat and often fatal. Established treatment options include conventional amphotericin B or one of its lipid-based or liposomal formulations, or a triazole antifungal such as fluconazole or itraconazole. [symbol: see text]Caspofungin (Cancidas--Merck Sharp & Dohme) and [symbol: see text]voriconazole (Vfend--Pfizer) are two new antifungals for severe infections caused by Candida spp. (invasive candidiasis) and Aspergillus spp. (invasive aspergillosis). Caspofungin is the first licensed echinocandin antifungal, while voriconazole is a triazole. Promotional claims for caspofungin include that it "provides an effective, yet less toxic, alternative to amphotericin B" while voriconazole is claimed to offer "significantly improved survival in invasive aspergillosis compared with amphotericin B". Here we consider the place of caspofungin and voriconazole in managing patients with severe fungal infections.     

Posaconazole as salvage therapy in a patient with disseminated zygomycosis: case report and review of the literature

Zygomycosis refers to any fungal infection originating from the class Zygomycetes and the order Mucorales. In immunocompromised patients, these fungi produce a relatively rapid, violently destructive, and highly fatal infection. Treatment approaches include both aggressive antifungal pharmacotherapy and surgical intervention. Unfortunately, even with optimal therapy, morbidity and mortality rates remain relatively high. As failure rates are elevated with commercial antifungals, new treatment options are needed. Posaconazole is an orally available, extended-spectrum triazole antifungal being investigated in phase III clinical trials for the treatment and prevention of invasive fungal infections, including zygomycosis. We report the case of a 26-year-old Vietnamese man with a medical history of acute lymphocytic leukemia who had undergone consolidation chemotherapy and had neutropenic fever when he came to the emergency department. The patient was admitted to the hospital and treated with broad-spectrum antibiotics and caspofungin. Two weeks into his admission, however, abscesses in the pelvis, prostate, and musculature surrounding the hip were detected radiographically; these abscesses eventually cultured for Mucor sp. Disseminated zygomycosis was diagnosed. Caspofungin was immediately discontinued, and high-dose liposomal amphotericin B 10 mg/kg/day was begun. Over the next month, infection spread to the right lung, left kidney, middle thoracic spine, and epidural space. As a result, oral posaconazole 200 mg 4 times/day was added to the liposomal amphotericin B. Significant clinical, hematologic, mycologic, and radiologic improvements were demonstrated as early as 10 days after start of posaconazole therapy and continued through 41 days of inpatient treatment. Liposomal amphotericin B was discontinued after 3 weeks of posaconazole, and the patient was discharged on hospital day 92 receiving oral posaconazole, with no major adverse events reported. Five months after discharge, the patient had no evidence of fungal disease recurrence or progression. Posaconazole appears to be a well-tolerated and effective salvage treatment for zygomycosis, including disseminated disease.     

Antifungal pharmacotherapy for invasive mould infections

The incidence of invasive mould infections is increasing and is associated with significant morbidity and mortality. Among the most prevalent of these infections are those caused by Aspergillus and Fusarium species. Invasive disease caused by moulds frequently presents as a pulmonary infection, but haematogenous infection can occur. Some moulds cause cutaneous disease through either direct inoculation of the skin or secondary spread to the skin after dissemination from another body site. Early diagnosis can often be difficult and, unfortunately, diagnosis occurs late in the course of illness in many cases. Treatment options have historically been limited by the need for intravenous administration (amphotericin B), significant toxicities (amphotericin B), lack of reliable in vitro activity (e.g., amphotericin B in Fusarium and Scedosporium apiospermum infections) and relative lack of clinical experience with newer agents. The recent approval of voriconazole (Vfend, Pfizer) introduces a treatment option that demonstrates both in vitro and in vivo activity against a variety of moulds. With the recent development of the new echinocandin class of antifungal agents and newer broad-spectrum azole antifungal agents with in vitro mould activity, there is a renewed emphasis on fungal treatment strategies. Antimould therapy presents challenges in adverse effect avoidance and management, drug interactions and pharmacoeconomic considerations. Furthermore, combination therapy is being explored with these various new antifungal agents. The administration of an optimal fungicidal therapy early in the course of the illness and control of the underlying disease are vital to prevent complications and mortality from these tenacious mycoses.     

Clinical pharmacokinetics of systemically administered antimycotics

Systemic fungal infections are a major threaten for immunocompromised patients. Beside the antimycotic spectrum, the pharmacokinetic properties of an antifungal drug are crucial for its clinical efficacy. Since patients with systemic mycoses frequently present with a significant co-morbidity, pharmacokinetics under special conditions such as renal insufficiency, renal replacement therapy or impaired liver function have to be considered. Amphotericin B is eliminated unchanged by the liver and the kidney. Its plasma protein binding accounts for 95 to 99 percent. Conventional amphotericin B deoxycholate has a remarkable infusion related and renal toxicity. Therefore, lipid formulations have been developed. By now, three lipid formulations are therapeutically used: liposomal amphotericin B, amphotericin B colloidal dispersion and amphotericin B lipid complex. Striking differences in their plasma pharmacokinetics have been found. These differences can be attributed to the diverse disposition of the lipid moieties, while liberated amphotericin B displays a pharmacokinetic behavior which is independent from the lipid-formulation applied. The highest amphotericin B tissue concentrations have been found in the liver and in the spleen, followed by lung, kidney and heart. Concentrations in brain tissue are very low. Flucytosine has no relevant protein binding and is eliminated by glomerular filtration. Fluconazole, itraconazole, voriconazole, posaconazole and ravuconazole are triazoles, used for treatment of systemic fungal infections. Significant drug interactions have to be considered during therapy with triazoles, particularly in patients dependent on immunosuppression. These interactions are caused by the metabolism of triazoles in the liver where the cytochrome P450 (CYP) system is involved at a different extend as well as by their mechanisms of action. Triazoles display a favorable tissue distribution with high penetration into the central nervous system. Echinocandins such as caspofungin and micafungin are rapidly taken up by peripheral tissues, particularly by the liver. In the first 24 hours this uptake appears to be the main route of elimination from plasma. Enzymatic degradation takes place, but is independent of CYP. Thus, drug interactions are a minor problem during echinocandin treatment. The highest tissue levels of caspofungin and micafungin have been measured in the liver. Moderate concentrations are achieved in lung, spleen and kidney. Penetration into the brain is relatively poor.     

Recent advances in antifungal chemotherapy

For over 50 years, amphotericin B deoxycholate (AmBD) has been the 'gold standard' in antifungal chemotherapy, despite its frequent toxicities. However, improved treatment options for invasive fungal infections (IFIs) have been developed during the last 15 years. Newer antifungal agents, including less toxic lipid preparations of AmBD, triazoles and the echinocandins, have been added to our armamentarium against IFIs. Some of these newer drugs can now replace AmBD as primary therapy (e.g. caspofungin for candidiasis, voriconazole for aspergillosis), whilst others offer new therapeutic options for difficult-to-treat IFIs (e.g. posaconazole for zygomycosis, fusariosis and chromoblastomycosis). It is interesting that extended use of newer antifungals such as fluconazole, despite decreasing the mortality attributed to candidiasis, resulted in selection of species resistant to several antifungals (Candida krusei, Candida glabrata); whilst several publications suggest that prolonged use of voriconazole may expose severely immunocompromised patients to the risk of zygomycosis (breakthrough). On the other hand, the differences in the mode of action of newer antifungals such as echinocandins raise the question whether combination antifungal therapy is more effective than monotherapy. Finally, the availability of an oral formulation with excellent biosafety of several newer antifungals (e.g. posaconazole) makes them candidates for prophylactic or prolonged maintenance therapy.     

Novel triazole antifungal agents

The risk of opportunistic infections is greatly increased in patients who are immunocompromised due to AIDS, cancer chemotherapy and organ or bone marrow transplantation. Candida albicans is often associated with serious systemic fungal infections, however other Candida species such as Candida krusei, Candida tropicalis and Candida glabrata, as well as Cryptococcus neoformans and filamentous fungi such as Aspergillus, have also emerged as clinically significant fungal pathogens. Two triazole antifungal agents, fluconazole and itraconazole, were introduced over a decade ago and since then have been used extensively for the prophylaxis and treatment of a variety of fungal infections. Although both drugs are effective and have their place in therapy, limitations regarding the utility of these agents do exist. For example, fluconazole is not effective for the prophylaxis or treatment of Aspergillus species and has limited activity against C. krusei and C. glabrata. The use of itraconazole has been limited secondary to concerns regarding unpredictable bioavailability. The rising incidence of fungal infections and the reported increase of non-albicans candidal infections noted over the past two decades highlight the need for new antifungal agents with improved spectra of activity. Several new triazole agents are in various phases of preclinical and clinical trials and may be available for human use in the near future. Three such agents voriconazole, posaconazole and ravuconazole are reviewed and compared with existing agents.     

Novel triazole antifungal agents

The risk of opportunistic infections is greatly increased in patients who are immunocompromised due to AIDS, cancer chemotherapy and organ or bone marrow transplantation. Candida albicans is often associated with serious systemic fungal infections, however other Candida species such as Candida krusei, Candida tropicalis and Candida glabrata, as well as Cryptococcus neoformans and filamentous fungi such as Aspergillus, have also emerged as clinically significant fungal pathogens. Two triazole antifungal agents, fluconazole and itraconazole, were introduced over a decade ago and since then have been used extensively for the prophylaxis and treatment of a variety of fungal infections. Although both drugs are effective and have their place in therapy, limitations regarding the utility of these agents do exist. For example, fluconazole is not effective for the prophylaxis or treatment of Aspergillus species and has limited activity against C. krusei and C. glabrata. The use of itraconazole has been limited secondary to concerns regarding unpredictable bioavailability. The rising incidence of fungal infections and the reported increase of non-albicans candidal infections noted over the past two decades highlight the need for new antifungal agents with improved spectra of activity. Several new triazole agents are in various phases of preclinical and clinical trials and may be available for human use in the near future. Three such agents voriconazole, posaconazole and ravuconazole are reviewed and compared with existing agents.     

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.     

Unlabeled uses of nebulized medications.

PURPOSE: The uses, dosing recommendations, benefits, and disadvantages of unlabeled drugs administered by nebulization are reviewed. SUMMARY: Nebulization is gaining popularity as a treatment alternative, and many drugs are used unlabeled in a nebulized form, including the opioids, lidocaine, magnesium sulfate, amphotericin B, and colistin. The opioids are frequently used to treat dyspnea in end-stage diseases. Common dosages include 1-2 mg every two hours as needed for hydromorphone and 25-50 microg every two hours for fentanyl citrate. Lidocaine can be used to relieve bronchoconstriction and cough symptoms as well as acting as a local anesthetic. It is typically given in a dose between 20 and 160 mg. Nebulized magnesium sulfate can be used in managing acute asthma and is given in dosages between 125 and 250 mg every 20 minutes, with no more than four consecutive doses. Nebulized amphotericin B can be used to prevent infections in immunocompromised patients. A typical amphotericin B regimen is 25 mg every 24 hours. Nebulized colistin is being studied in the prevention and treatment of gram-negative infections and in patients awaiting lung transplants. Colistin is often given as 75 mg every 12 hours to combat infections. CONCLUSION: Unlabeled nebulization of opioids, lidocaine, magnesium, amphotericin B, and colistin is an alternative method of treatment for patients with pulmonary problems or infections or for those undergoing bronchoscopy. More research is needed to develop guidelines for their use since nebulization may provide benefits to many patients who otherwise cannot be treated or would be at risk of systemic adverse effects of the drugs.     

New investigational antifungal agents for treating invasive fungal infections

Systemic fungal infections have been recognised as a major cause of morbidity and mortality during the last two decades. There are only a few therapeutic options for these infections. Severe toxicity, such as impairment of renal function, limits the use of amphotericin B. Flucytosine is associated with side effects and drug resistance. Fluconazole and itraconazole are safer, though emergence of resistance and innate resistance in some fungal pathogens is a concern in their use. Therefore, there is a need for developing novel drugs and/or treatment strategies to combat these infections. In recent years, increased efforts by the pharmaceutical industry and academia have led to the discovery of new re-engineered or reconsidered antifungal agents that are more efficacious, safer and have a broad spectrum of activity. Lipid formulations of polyene antifungal agents, amphotericin B and nystatin, have the advantage of improved therapeutic index. Activity against resistant fungi, high bioavailability, safety and longer half-life are the properties that encourage development of the newer triazoles (e.g., voriconazole, ravuconazole and posaconazole). Echinocandin-like lipopeptide antibiotics are among the antifungal agents with a novel mode of action. In addition to these lead investigational compounds, development of newer antifungal agents is underway.     

New investigational antifungal agents for treating invasive fungal infections

Systemic fungal infections have been recognised as a major cause of morbidity and mortality during the last two decades. There are only a few therapeutic options for these infections. Severe toxicity, such as impairment of renal function, limits the use of amphotericin B. Flucytosine is associated with side effects and drug resistance. Fluconazole and itraconazole are safer, though emergence of resistance and innate resistance in some fungal pathogens is a concern in their use. Therefore, there is a need for developing novel drugs and/or treatment strategies to combat these infections. In recent years, increased efforts by the pharmaceutical industry and academia have led to the discovery of new re-engineered or reconsidered antifungal agents that are more efficacious, safer and have a broad spectrum of activity. Lipid formulations of polyene antifungal agents, amphotericin B and nystatin, have the advantage of improved therapeutic index. Activity against resistant fungi, high bioavailability, safety and longer half-life are the properties that encourage development of the newer triazoles (e.g., voriconazole, ravuconazole and posaconazole). Echinocandin-like lipopeptide antibiotics are among the antifungal agents with a novel mode of action. In addition to these lead investigational compounds, development of newer antifungal agents is underway.     

Antifungals in systemic neonatal candidiasis

Fungal infections are common in the newborn period, especially among premature neonates, and are responsible for considerable morbidity and mortality. Currently, three classes of antifungals are commonly used in the treatment of systemic fungal infections in neonates: the polyene macrolides (e.g. amphotericin B [deoxycholate and lipid preparations]); the azoles (e.g. fluconazole); and the fluorinated pyrimidines (e.g. flucytosine). The echinocandins (e.g. caspofungin and micafungin) are a newer class of antifungals which shows promise in this population.The available kinetic data on amphotericin B deoxycholate in neonates are derived from very small studies and exhibit considerable variability. There are no kinetic data available for the use of lipid preparations in this population and, again, much has been inferred from adult studies. The information available for flucytosine is also limited but appears similar to what is observed in adults. Fluconazole has the most neonatal pharmacokinetic data, which show slightly less variability than the other antifungals. Genomic factors which affect the metabolism of amphotericin B and fluconazole may explain some of the observed variability.Most of the data for the efficacy of antifungal drugs in neonates are derived from retrospective studies and case reports. The data for amphotericin B deoxycholate and flucytosine are limited. There are more data for the liposomal and lipid complex preparations of amphotericin B and for fluconazole in this population. These support the use of these drugs in neonates, but because of their largely noncomparative nature they can not define the optimal dosage or duration of therapy.Amphotericin B deoxycholate is primarily nephrotoxic. It also induces electrolyte abnormalities and is to a lesser degree cardiotoxic. This toxicity in neonates appears similar to published data in older children and adults. While the lipid preparations of amphotericin B owe their existence to a presumed decrease in toxicity, the observed toxicity in neonates appears to be equal to that seen with the deoxycholate, although it should be noted that the lipid preparations are usually given at much higher dosages. Fluconazole toxicity appears to be milder and less frequent in this population than is seen with amphotericin B.In the final analysis, we do not have sufficient data to define the pharmacokinetic profiles, optimal dose or duration of therapy, or toxicity for any of these compounds in neonates. Further studies are necessary if the optimisation of antifungal therapy in this population is to continue.     

Zygomycosis: an emerging fungal infection.

PURPOSE: The epidemiology, pathogenesis, clinical presentation and diagnosis, and management of zygomycosis are reviewed. SUMMARY: The frequency of zygomycosis has been increasing over the past 10 years; infections have been identified in up to 6.8% of patients at autopsy. The most common route of transmission for Zygomycetes fungi is inhalation of spores from the environment. Patients at highest risk for infections caused by Mucorales fungi include those with profound immunosuppression or diabetes, intravenous drug abusers, premature infants, those receiving deferoxamine, and recipients of bone marrow transplants. Mucormycosis commonly presents as rhinocerebral or pulmonary disease; gastrointestinal presentations also occur. Clinical manifestations of invasive mucormycosis are tissue necrosis and subsequent thrombosis. Common features of pulmonary disease include fever, dyspnea, hemoptysis, and cavitation upon radiologic examination. The mainstays of treatment are control or reversal of the underlying disease or immunosuppression, antifungal therapy, and aggressive surgical debridement. Posaconazole, a new triazole antifungal, has been used successfully in a number of cases that did not respond to amphotericin B. CONCLUSION: Zygomycosis appears to be on the rise in the United States. The standard treatment is a combination of amphotericin B therapy, surgical debridement, and reversal of the underlying disease or immunosuppression.     

Lipid-based amphotericin B: a review of the last 10 years of use

The last decade has been remarkable for the dramatic increase in the prevalence of serious fungal infections in patients with haematological disorders and neutropenic cancer patients. The mortality rate of deep-seated infection has been in excess of 90% and there is no doubt that this is one of the greatest challenges currently facing haematologists and oncologists. The development of the lipid-based drugs - liposomal amphotericin (AmBisome(R)), amphotericin B lipid complex, ABLC (Abelcet(R)), amphotericin B colloidal dispersion, Amphocil (ABCD(R)), has meant that doses of amphotericin B can be safely escalated for the first time whilst the problems of nephrotoxicity, infusion related reactions (including chills, rigors, fevers and hypoxia) can be reduced. These toxicities are variably reduced with AmBisome more than Abelcet and more than Amphocil and there is little information from randomised trials other than for AmBisome. AmBisome used in the setting of persistent fever and neutropenia not responding after 3-4 days of intravenous antibiotics, is associated with less breakthrough systemic fungal infections. There is also much less need for premedication, including steroids, compared with amphotericin B and Abelcet. The use of intermittent doses of Ambisome given prophylactically is now being explored. A new and exciting era of antifungal therapy is opening up with new compounds, such as itraconazole voriconazole, posaconazole and echinocandins, being investigated and for the first time, we also have options for combination therapy and prophylaxis.     

Démarche diagnostique et prise en charge des infections fongiques chez les patients immunodéprimés

The frequency of invasive mycosis has been in increase for 20 years because of the multiplication of invasive procedures and immunosuppressive treatments. The recent publication of the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) definitions has provided an international standard for the performance of clinical research in this group of patients. The definitions committee has now been reconvened to consider some of the criticisms of the original criteria and these are likely to evolve further in the future. The latter grew rich these last years by the search for antigen by ELISA for invasive aspergillosis. Other antigen research for Candida and is in the course of evaluation like the ß-glucan. In vitro antifungal susceptibility of fungi must be reserved for the situations of major infections. On the therapeutic level, the new lipidic formulations of the amphotericine B allowed a clear reduction in the side effects. The voriconazole has a broad spectrum containing filamentous yeasts and fungi. In the same way, the posaconazole also makes it possible to treat aspergillosis and other rare filamentous fungi. Lastly, caspofungin, first representative of a new class of antifungal echinocandins, was also marketed. The current tendency, in the treatment of the invasive candidosis, is with generalization of the use of fluconazole even in the unstable patient, in particular because of its excellent tolerance and of its cost. The treatment is then to adapt according to the identification of the strain. In invasive aspergillosis, the treatment of first line is voriconazole. In second intention, in the event of non favorable evolution, of side effects and/or medicamentous incompatibilities requiring a change of therapeutics, the recommended treatment is the liposomal amphotericin B or caspofungin. The increasing use of the new molecules tends to reduce the indications of the traditional amphotericin B.