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netherlands journal of critical care System and reported that Candida albicans was one of the most frequently isolated pathogens in patients with device-associated nosocomial infections, with a rate of 11.2 per 100 [18]. Regarding the specific situation in the <strong>Netherlands</strong>, no detailed information is currently available. A national surveillance program on nosocomial infections in 16 hospitals was published in the Dutch medical journal (NTVG) in 2001, but this paper did not report the incidence of specific causative pathogens such as Candida [19]. However, the results of the Europe-wise EPIC study strongly suggested that the incidence of yeast infections was high in all participating countries, though the overall infection rates were higher in Southern Europe than Northern Europe. Thus the available evidence strongly suggests that yeast and fungal infections present a significant clinical problem in critically ill ICU patients. Moreover, the number of yeast infections seems to be slowly but steadily increasing over the past few years [1-3]. Candidaemia is frequently associated with a sepsis syndrome, and often involves presence of disease outside of the bloodstream [20- 21]. Mortality of the disease is high even when the initial treatment is adequate [1-5,20,21]; this problem is compounded by the fact that antifungal therapy may not be adequate in many cases. For example, Morgan et al. reported in a surveillance study that of the patients in whom Candidaemia was found 30%–39% received inadequate treatment (usually the problem was too short duration of treatment, i.e. less than 7 days), and that 10% of patients received no therapy at all [22]. This problem is further compounded by the fact that Candida species are relatively difficult to culture, and thus diagnostic testing for susceptibility to antifungal drugs may take long; in addition diagnostic testing for Candida can be unreliable, and thus the incidence of Candida infections may be underestimated [23]. Aspergillus infections occur far less frequently. However, they are by no means rare; up to 7% of patients dying in European teaching hospitals have invasive Aspergillosis, often but not always in the context of some form of immune suppression [24-26]. Fungal IL6 CRP Pyrexia HSP90 NO In recent years, a protein called heat shock protein 90 (HSP90) has emerged as a completely novel target for antifungal treatments. HSP90 is a molecular chaperone with various complex cellular func- Vasodilatation Platelet Malfunction Figure 1. Role of HSP 90 in vasodilation and septic shock. Human Bradykinin Hypotension Currently, four classes of antifungal drugs are available for treatment of systemic yeast and fungal infections (Table 1, references 1-5, 27- 35). These are the polyenes (amphotericin-B), the azoles (ketoconazole, itraconazole, fluconazole, and voriconazole), flucytosine, and echinocandin antifungal drugs such as caspofungin. Amphotericin-B, the first drug to treat systemic fungal infections (available since the end of the 1950’s) is still a highly effective broadspectrum antifungal agent; it remains the gold standard to which other treatments are compared. The main problems associated with its use are its potentially severe side effects, which include nephrotoxicity as well as acute toxic reactions and other infusion related side effects. Lipid-based and liposomal forms of amphotericin B (Abelcet ® and Ambisome ® ) were developed in the 1990’s has may have fewer side effects than “normal” amphotericin B, though this remains a matter for debate and the relatively high costs of these drugs has somewhat limited their use. Agents from the azole category have been available since the 1980’s, and have gained popularity because their toxicity and risk of side effects is far lower than is the case for amphotericin B. A potential disadvantages of azole regimens is that many azoles are not effective against Aspergillus species; in addition, many drugs from the azole group inhibit fungal growth in susceptible organisms (fungistatic effect) but may not eliminate fungi as effectively as amphotericin B (fungicide effect). However, recent studies suggest that regimens including voriconazole, the latest agent from the azole category to reach the market, may be equally effective as regimens including amphotericin B (30). Another important addition to the therapeutic arsenal of antifungal drugs is the category of echinocandins, which include drugs such as caspofungin, micofungin and anidulafungin (27,34-35). Echinocandins specifically inhibit the synthesis of beta (1-3)glucan, a protein that is specific to the cell walls of yeasts and fungi and is not found in mammalian cell walls. Echinocandins have a fungicide effect in Candida species and a fungistatic effect in Aspergillus species. Because the mechanism of action is different from that of other antifungal drugs, combination treatments with drugs from other categories would be feasible. In spite of all the recent improvements and additions to the therapeutic arsenal, invasive fungal infections in critically ill patients still present a formidable problem. For example, even in recent studies in patients with invasive Candida infections who were receiving adequate treatment (comparing novel treatments with echinocandins or voriconazole to “conventional” amphotericin B), Candida-attributable mortality still ranged from 4.4-8.7%; in untreated patients or those receiving inadequate treatment mortality ranges of 15%-49% have been reported in matched case-control studies. As described above, various studies have shown that initial antifungal therapy is often inadequate (22), with an associated high mortality. Cure rates could be improved by combining different treatment regimens but this strategy could be hampered by side effects, particularly those associated with use of amphotericin B. In addition, drug resistance is becoming an increasing problem (1-5). This includes both an increase in fungal drug resistance and a shift from infections caused by Candida albicans, which is usually highly susceptible to antifungal treatment, to non-albicans infections that are less easy to treat such as Candida glabrata and Candida kruzei (1,3). 588 neth j crit care • volume 10 • no 5 • october 2006
netherlands journal of critical care tions. Briefly, it allows cells and organisms to cope with protein folding defects that arise from insults including mutations and environmental stress. In humans the release of HSP90 from injured cells or micro-organisms and lead to NO-mediated vasodilation and shock (Figure 1). HSP90 has raised significant interest as a potential target of anti-cancer treatments (36-40). However, this paper will not deal with this issue, focussing instead on the role of HSP90 in fungal infections and as a potential target of anti-fungal therapy. Recent studies have shown that HSP90 is crucial for the survival of a fungal cell, and that it also plays a key role in the development of drug resistance (41-42). Conversely, inhibition of HSP90 significantly increases fungal susceptibility to various drug treatments. For example, addition of HSP90 can allow fungistatic drugs from the azole group such as fluconazole to become fungicidal, i.e. fully lethal to yeasts and fungi (42). The key role of HSP90 in the development of fungal infections and drug resistance make it an ideal target for antifungal drugs. This applies particularly because in humans HSP90 should not be present outside the cell or on the cell wall; this means that, in theory, inhibition of HSP90 should not cause significant side effects. Inhibition of HSP90 would have a three-pronged approach, simultaneously hampering fungal replication, increasing efficacy of antifungal treatment and decreasing the risk of developing resistance to antifungal drugs. An anti-HSP90 drug, more specifically a human genetically recombinant antibody to HSP90, has recently been developed and tested in various small and medium-sized clinical trials (43-51). The potential clinical applications of this novel drug, called Mycograb ® , include all invasive mycoses. It is intended for use in combination treatments, i.e. it should always be combined with one of the traditional or novel antifungal drugs listed above. Pre-clinical studies have demonstrated that Mycograb ® binds to and inactivates HSP90 present in the fungal cell wall and in extra cellular material, particularly around foci of infection. The latter effect may provide additional benefits in the clinical setting in infected patients, by reversing HSP90-mediated vasodilatation and inflammation. The aim of the round table meeting was to assess the currently available evidence for the use of Mycograb ® and to discuss the potential place of Mycograb ® in the treatment of severe yeast-and fungal infections in the general ward and especially the intensive care setting. Round Table meeting The meeting started at 18.30 with a brief introduction by the chairmen, Kees Polderman, internist-intensivist from the VU medical center in Amsterdam and Arthur van Zanten, internist-intensivist from the Gelderse Vallei hospital in Ede. After the participants had briefly introduced themselves the meeting began with opening statements from three representatives of Neutec Company, the sponsor of the meeting. The first speaker, George Heron, provided some background information about Neutec Pharma Company. NeuTec Pharma is a small company founded in 1998 that is situated in the United Kingdom. It is in the process of developing three drugs, all recombinant antibodies: Mycograb ® for the treatment of severe fungal Infections, Aurograb ® for the treatment of severe staphylococcal infections (currently being tested in a phase III trial in Europe) and Enterograb ® for the treatment of symptomatic Clostridium difficile infections. The latter drug is still in the stage of preclinical development. A few weeks after the organisation of this round table meeting, NeuTec pharma was acquired by Novartis AG, which will thus be handling the further development and marketing of Mycograb ® and other Neutec products. Mycograb ® was first tested clinically in 2003. A phase IIb confirmatory study was completed in 2004. Recently, a confirmatory study was published in clinical and infectious diseases (50). A summary of this study was provided by one of the subsequent speakers, Dr. Spronk from Apeldoorn, The <strong>Netherlands</strong>, who participated in this study. The first lecture was concluded with a summary of Mycograbs’ potential applications and advantages. The target group should be patients with invasive fungal infections at high risk for mortality; it should be used in a combination regimen and not as a single drug therapy; potential advantages include improved outcome, lower morbidity, low risk of side effects and prevention of resistance to current and new drugs. In addition, it might allow use of lower doses of existing drugs without decreasing the therapeutic efficacy. Mycograb ® was given Orphan Drug status in both Europe and the United States. Submission for marketing in Europe was submitted to the European Medicine Evaluation Agency (EMEA) in 2005; at the time of the round table meeting approval was still pending, a decision is expected shortly. The next speaker was doctor Polderman, who provided background information on the problem of Candida infections in the ICU and on the currently available anti-fungal drugs. The information provided in this lecture is summarised in the introduction section of this paper. The third and final speaker was Dr. Spronk from the Gelre hospital in Apeldoorn. As stated above dr. Spronk was one of the coauthors of the latest study with Mycograb ® (50). Dr. Spronk summarized the results of this study as an introduction to the round table discussion. The study objective of this double-blind placebo-controlled randomised study was to determine the efficacy and safety of Mycograb ® combined with liposomal amphotericin B versus liposomal amphotericin and placebo. Patients with culture-confirmed invasive Candidiasis (sub-divided into patients with Candida albicans or nonalbicans) were included in the study. Each patient received Abelcet ® (5 mg/kg daily for at least 10 days) or Ambisome ® (3 mg/kg daily for a minimum of 10 days). Patients also received either Mycograb ® (1mg/kg body weight twice daily for 5 days) or placebo. Efficacy was assessed using both clinical criteria and mycological responses (using cultures taken every day from day 2 after beginning of treatment or until all signs of infection had disappeared and cultures were repeatedly negative). Assessment of clinical response was made by the local investigator and considered complete if all signs and symptoms thought to be due to the Candida infection had resolved completely. Adverse events were also monitored by an independent expert and safety monitoring committee. The results showed a significant improvement in clinical response rate associated with Mycograb®, with a 86% favourable response in patients treated with a combination of amphotericin B and Mycograb neth j crit care • volume 10 • no 5 • october 2006 589
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