Fungal infections: diagnostic problems and choice of therapy.

Fungi are typically opportunistic pathogens. Formerly, limitations in diagnostic techniques explain why invasive fungal infections are usually detected in a late stage of their development. Therefore, traditional guidelines dictate antifungal treatment for all patients with persisting fever. This is not longer justifiable in view of the potential adverse events and the economical burden associated with the use of the new antifungal drugs in an era with improved diagnostic tools. Amphotericin B has been the drug of choice for invasive fungal infections for more than 30 years. Owing to nephrotoxicity, its use in neutropenic patients has been largely abandoned in favor of a lipid formulation of amphotericin B, of which only liposomal amphotericin B has been scientifically tested in the first-line treatment of aspergillosis. Azoles constitute an acceptable alternative to intravenous amphotericin B for many invasive fungal infections.

European expert opinion on the management of invasive candidiasis in adults.

This report discusses the present status of antifungal therapy and treatment options for candidaemia, considered by experts in the field in Europe. A conference of 26 experts from 13 European countries was held to discuss strategies for the treatment and prevention of invasive candidiasis, with the aim of providing a review on optimal management strategies. Published and unpublished comparative trials on antifungal therapy were analysed and discussed. Commonly asked questions about the management of candidaemia were selected, and possible responses to these questions were discussed. Panellists were then asked to respond to each question by using a touchpad answering system. After the initial conference, the viewpoint document has been reviewed and edited to include new insights and developments since the initial meeting. For many situations, consensus on treatment could not be reached, and the responses indicate that treatment is likely to be modified on a patient-to-patient basis, depending on factors such as degree of illness, prior exposure to azole antifungals, and the presence of potentially antifungal drug-resistant Candida species.

Impact of alternate definitions of fever resolution on the composite endpoint in clinical trials of empirical antifungal therapy for neutropenic patients with persistent fever: analysis of results from the Caspofungin Empirical Therapy Study.

BACKGROUND: Sensitivity analyses were incorporated in a Phase III study of caspofungin vs. liposomal amphotericin B as empirical antifungal therapy for febrile neutropenic patients to determine the impact of varying definitions of fever resolution on response rates. METHODS: The primary analysis used a 5-part composite endpoint: resolution of any baseline invasive fungal infection, no breakthrough invasive fungal infection, survival, no premature discontinuation of study drug, and fever resolution for 48 h during the period of neutropenia. Pre-specified analyses used 3 other definitions for fever resolution: afebrile for 24 h during the period of neutropenia, afebrile at 7 days post therapy, and eliminating fever resolution altogether from the composite endpoint. Patients were stratified on entry by use of antifungal prophylaxis and risk of infection. Allogeneic hematopoietic stem cell transplants or relapsed acute leukemia defined high-risk patients. RESULTS: In the primary analysis, 41% of patients in each treatment group met the fever-resolution criteria. Low-risk patients had shorter durations of neutropenia but failed fever-resolution criteria more often than high-risk patients. In each exploratory analysis, response rates increased in both treatment groups compared to the primary analysis, particularly in low-risk patients. CONCLUSIONS: Response rates for the primary composite endpoint for both treatment groups in this study were driven by low rates of fever resolution. Requiring fever resolution during neutropenia in a composite endpoint can mask more clinically relevant outcomes.

[Improved diagnostics in invasive aspergillosis and systematic monitoring in patients at high risk of infection]. / Verbeterde diagnostiek van invasieve aspergillose en systematische controle bij patiënten met een verhoogd risico.

Invasive aspergillosis remains an important cause of morbidity and mortality in patients with prolonged and severe immune suppression such as following haematopoietic stem-cell transplantation. Consensus definitions, which allow categorisation of patients based on diagnostic criteria, are an important improvement in uniform registration of invasive mycoses in clinical trials. Prospective monitoring of high-risk patients for the circulating aspergillus cell-wall component galactomannan, results in earlier diagnosis in two-thirds of patients when compared with conventional diagnostic methods. High-resolution CT (HRCT) enables the lesions characteristic of invasive mycoses to be detected earlier and better than by chest radiograph. In addition, invasive mycoses cause characteristic lesions on the HRCT scan including the halo-sign and the air-crescent sign. The pre-emptive management strategy which combines monitoring of patients for surrogate markers with a HRCT scan appears to be a promising approach to the early identification and treatment of patients with invasive aspergillosis.

Prospective evaluation of gut mucosal barrier injury following various myeloablative regimens for haematopoietic stem cell transplant.

We determined gut mucosal barrier injury (MBI) among 129 recipients of an allogeneic or autologous haematopoietic stem cell transplant (HSCT) who had been given different myeloablative regimens by measuring integrity using the lactulose/rhamnose (RHA) ratio and absorption using the ratios of rhamnose/3-O-methylglucose and xylose/3-O-methylglucose. Regimens that did not contain idarubicin induced oral mucositis and disturbed gut integrity and absorption earlier than did those containing the anthracycline. By contrast, regimens containing idarubicin induced more severe and prolonged oral and gut MBI. Gut integrity and absorption of most patients were still abnormal at discharge from hospital. These results confirm that the integrity and absorptive capacity of the gut is affected adversely by myeloablative regimens in general, although only two patterns of mucosal injury emerged depending on whether or not idarubicin was used.

An open multicentre comparative study of the efficacy, safety and tolerance of fluconazole and itraconazole in the treatment of cancer patients with oropharyngeal candidiasis.

Oropharyngeal candidiasis is a frequent infection in cancer patients who receive cytotoxic drugs. In this study, the efficacy, safety and tolerance of fluconazole and itraconazole were compared in non-neutropenic cancer patients with oropharyngeal candidiasis. Of 279 patients who were randomised between the two treatment groups, 252 patients were considered to be eligible (126 in each group). The clinical cure rate was 74% for fluconazole and 62% for itraconazole (P=0.04, 95% Confidence Interval (CI): 0.5-23.3%). The mycological cure rate was 80% for fluconazole and 68% for itraconazole (P=0.03, 95% CI: 1.2-22.6%). The safety and tolerance profile of both drugs were comparable. This study has shown that in patients with cancer and oropharyngeal candidiasis, fluconazole has a significantly better clinical and mycological cure rate compared with itraconazole.

Measuring mucosal damage induced by cytotoxic therapy.

We scored oral mucositis and gut toxicity and measured sugar permeability testing among 56 recipients of a haematopoietic stem cell transplant (HSCT) given myeloablative conditioning with idarubicin, cyclophosphamide and TBI, and a group of 18 patients given cytotoxic chemotherapy for newly diagnosed acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS). Gut integrity was already disturbed in the AML/MDS group as measured by the lactulose/rhamnose ratio (L/R ratio=0.09) before therapy and was severely perturbed (L/R ratio >0.13) for a month after HSCT. Oral mucositis and to a lesser extent gut toxicity was only significantly correlated with disturbed permeability in the transplant group. The data suggest that sugar permeability, oral mucositis and gut toxicity measure different features of mucosal damage after intensive cytotoxic therapy.

Voriconazole-a new therapeutic agent with an extended spectrum of antifungal activity.

Voriconazole is a new antifungal agent that can be given orally and intravenously. It has proven efficacy for treating candidosis and invasive aspergillosis as well as other mould infections, such as those caused by Fusarium and Scedosporium spp. The drug is generally well tolerated.

Feasibility of a new in vitro approach to evaluate cellular damage following co-infusion of red blood cell concentrates and intravenous drug solutions.

INTRODUCTION: Transfusion guidelines may result in unwanted delay in infusion schemes, as simultaneous infusion of blood components and drug solutions is universally prohibited. The aim of this study was to measure possible damage to red cells by drug solutions, as manifested by haemolysis, using a dynamic model that resembles the clinical setting. METHODS: Stored filtered and irradiated RBC concentrates and drug solutions were co-infused in an in vitro dynamic model. Also, incubation in a static model was performed. The haemolytic potency of the drug solutions was measured by determining free haemoglobin (fHb) levels. RESULTS AND DISCUSSION: Neither in the dynamic tests nor in the static tests did fHb levels exceed the maximally acceptable standard for filtered RBC concentrates according to Dutch specification guidelines. In the static test model, fHb levels were slightly elevated compared with those of control samples, as well as those in the dynamic test model. CONCLUSION: A novel in vitro dynamic infusion system appears to represent a useful technique to calculate possible damage to RBCs resulting from co-infused drug solutions. Co-infusion of the drug solutions tested with filtered and irradiated RBC concentrates did not produce fHb levels above the levels accepted by the Dutch national guidelines. Apart from haemolysis, other parameters reflecting RBC damage should be investigated in future studies.

Aspergillus galactomannan antigen levels in allogeneic haematopoietic stem cell transplant recipients given total parenteral nutrition.

False-positive tests for Aspergillus galactomannan have been reported in neutropenic patients. We failed to detect any circulating antigen during the 2 weeks following allogeneic haematopoietic stem cell transplantation of 12 patients who had severe mucositis but were unable to eat.

Achievements and goals of the EORTC Invasive Fungal Infections Group. European Organisation for Research and Treatment of Cancer.

Invasive fungal infections are an increasing complication for patients with cancer. These infections still are difficult to diagnose and to treat and thus still have a high fatality rate. New strategies should include evaluation of new diagnosis tools and large-scale assessment of these new methods will need multidisciplinary collaboration. High-quality clinical trials dedicated to establish 'state-of-the-art' prevention and treatment are also directly needed. Created in 1991, the EORTC Invasive Fungal Infection Group has faced several of these challenges and significantly improved the knowledge and management of these infections in Europe.

Empirical therapy of febrile neutropenic patients with mucositis: challenge of risk-based therapy.

Nowadays Gram-positive cocci, especially oral viridans streptococci (OVS) and coagulase-negative staphylococci (CoNS), are the most common bloodstream isolates in febrile neutropenic patients. Although in general these cocci are quite indolent, Streptococcus mitis is associated with serious complications such as sepsis and/or adult respiratory distress syndrome. Neutropenia is the most significant predisposing factor but the impact of mucositis, i.e. damage to the mucosal barrier of mouth and intestines (mucosal barrier injury, MBI), is very much greatly underestimated. Oral mucositis is a strong predictor of OVS bacteremia and simultaneously CoNS bacteremia is clearly associated with mucositis. Treatment with especially high dose cytarabine, cyclophosphamide and idarubicin, when given to allogeneic hematopoietic stem cell transplant recipients, predictably results in mucositis. Hence, the occurrence of mucositis should have implications for complementing empirical therapy with specific drugs such as glycopeptides, because risk patients can be selected based upon the chemotherapeutic therapy administered. An algorithm is presented for dealing with patients at high risk of mucositis and bacteremia due to Gram-positive cocci.

Need for alternative trial designs and evaluation strategies for therapeutic studies of invasive mycoses.

Studies of invasive fungal infections have been and remain difficult to implement. Randomized clinical trials of fungal infections are especially slow and expensive to perform because it is difficult to identify eligible patients in a timely fashion, to prove the presence of the fungal infection in an unequivocal fashion, and to evaluate outcome in a convincing fashion. Because of these challenges, licensing decisions for antifungal agents have to date depended heavily on historical control comparisons and secondary advantages of the new agent. Although the availability of newer and potentially more effective agents makes these approaches less desirable, the fundamental difficulties of trials of invasive fungal infections have not changed. Therefore, there is a need for alternative trial designs and evaluation strategies for therapeutic studies of invasive mycoses, and this article summarizes the possible strategies in this area.

Reliability of clinical research on invasive fungal infections: a systematic review of the literature.

The aim of this study was to assess the comparability and reliability of clinical research on invasive fungal infections (IFIs) which is accumulating in the medical literature. A Medline search strategy was developed covering the years 1985-1997. The 7,086 articles identified this way were further limited to 173 by reading the abstracts to studies involving immunocompromised patients and deep tissue infections. Diagnostic criteria used for definitions of IFIs were evaluated according to the level of confidence in diagnosis. For analysing the reliability, we used the sample of 397 patients from the European Organization for Research and Treatment of Cancer (EORTC) database. Each patient in the database was evaluated according to the definitions employed in each article. The level of overall agreement among the articles was very low (Kappa = 0.253). The results of this analysis show the discrepancy in the medical literature in diagnosing IFIs and the necessity for the standardization of definitions.

Treatment of documented and suspected neutropenia-associated invasive fungal infections.

Factors such as the intensification of anti-tumor regimens have enhanced both the depth and length of neutropenia and endorsed severe deficiencies in other immune systems. As a result, the risk of fungal infections has increased substantially. Clinicians should be aware of the possibility to enable a timely diagnosis because many of the problems in the management of invasive fungal infections during neutropenia are as much the consequence of diagnostic short-comings as of lack of therapeutic options. About 7% of all febrile episodes during neutropenia can ultimately be attributed to fungi, Candida and Aspergillus species being the paramount pathogens. Although the data in favor of prophylactic use of antifungals are not convincing, prophylaxis is still recommended in an attempt to protect particularly high-risk patients. Fluconazole still appears a suitable agent in recipients of a bone marrow transplant. Given the paucity of data, reappraisal of the value of empirical antifungal therapy is warranted. Amphotericin B with or without 5-flucytosine is considered the standard therapy for acute candidiasis with fluconazole as an alternative. Amphotericin B is also first-line therapy for invasive aspergillosis in neutropenic patients; lipid-based formulations are recommended for patients who develop nephrotoxity. Recovery of the granulocytes and other immune systems has shown to be of critical importance in the management of all invasive fungal infections.

Regional Variations in the Further Management of Neutropenic Patients already Receiving Empirical Antimicrobial Therapy.

To investigate whether or not the considerable regional differences in prescribing further modifications to initial empirical regimen were due to differences in the patient populations or were the result of other factors we re-analysed the data from a large multicentre study of monotherapy for the empirical treatment of febrile, neutropenic patients. We matched 151 episodes treated in 14 centres in Europe with the same number treated in 17 centres in North America for age > 46 years, gender, acute leukaemia, antibacterial prophylaxis, intravascular catheter use, receipt of ceftazidime or piperacillin plus tobramycin which were the regimens in the original study, the presence of bacteraemia at the onset of fever and the occurrence of a focus of infection within the first 3 days of empirical therapy. The initial regimen was in fact unchanged and successful after 72h for 74% of episodes treated in European centres and 45% of those treated in North American centres (p <.0001) and 38% and 21% of episodes respectively were managed successfully without any modification of therapy (p =.0044). Amphotericin and acyclovir were given in 35% and 11% of episodes treated in European centres compared with 53% and 25% of episodes treated in North American centres (p =.0053 and.0029). Moreover, empirical therapy was changed after a mean 4.8 days (95% Cl± 0.8) in North American centres but after 7.1 days (95%CI±1.0) in European centres (p =.0004) and there were 2.3±0.3 changes to therapy compared with 1.5±0.3 changes respectively (p =.0002). However there was no significant difference in survival (97% in and 96%), in the number of episodes complicated by a subsequent infection (10% and 11%), in the incidence of other adverse event (11% and 10%) nor in the proportion of episodes in which fever persisted longer than 5 days (53% and 48%) in North American centres and European centres respectively. The duration of fever (8.4±1.4 days and 7.1 ±1.2 days), antimicrobial therapy (19.8±1.9 days and 16.3±1.5 days) and neutropenia <0.5×10(9)/L (19.9±2.9 days and 16.8±2.1 days) were also similar for North American centres and European centres respectively. These results suggest a genuine regional difference in medical practice does, in fact, exist.

Procalcitonin does not discriminate infection from inflammation after allogeneic bone marrow transplantation.

Procalcitonin (PCT) is an early marker of bacterial infection but little is known about its value in neutropenic allogeneic bone marrow transplant (BMT) recipients. We collected plasma from 12 recipients of T-cell-depleted HLA-matched related BMT recipients who had been treated preemptively with meropenem from the day after BMT for at least 15 days. PCT and C-reactive protein (CRP) concentrations were determined on BMT days 1, 5, 8, 12, and 15, and their relationship to inflammatory events (IE), including mucositis, microbiologically and clinically defined infections, acute graft-versus-host disease (GVDH), and unexplained fever, was then determined. The PCT concentrations were all low and never exceeded 4 microg/liter, unlike CRP concentrations, which spanned the full range up to 350 mg/liter. All patients had mucositis, and there was no significant difference between PCT concentrations associated with mucositis alone and those associated with an additional IE on BMT days 1 to 12. However, on BMT day 15, the mean concentrations of PCT were 0.37 +/- 0.05 microg/liter for the 10 patients that had an additional IE, compared with 0.11 +/- 0.03 microg/liter for the 2 patients with mucositis only (P = 0.012), and GVHD rather than infection was involved in six cases. PCT was also not a sensitive marker of gram-positive bacteremia or pulmonary aspergillosis. Thus, PCT is of little value in discriminating infections from other inflammatory complications that occur following allogeneic BMT.

New antifungal agents and preparations.

In neutropenic patients amphotericin B remains the drug of choice for the treatment of systemic fungal infections. On the basis of a superior efficacy in combination with a lower toxicity, the triazoles have superseded the older azoles. Regularly, amphotericin B and a triazole are used simultaneously without any evidence from clinical trials that such a strategy is safe and efficacious. Liposomal preparation, lipid complex or colloidal dispersion of amphotericin B have been produced successfully to reduce toxicity. However, there is only one small randomised study that hints at the superiority of liposomal amphotericin B over amphotericin B deoxycholate. Promising new agents like candins, sordarins, high dose oral terbinafine, the third generation azoles, and liposomal nystatin are under development. The first phase II study on voriconazole in the treatment of pulmonary aspergillosis has produced encouraging results. The major promise of the new candins lies in the activity against Candida species, including those resistant to the azoles and polyenes, and in a mechanism of action totally different from the established antifungals. Cytokines and colony stimulating factors are theoretically very promising but there are no clinical studies that warrant routine use.