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Published on 1 July 2007

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Focus on antifungals at Europe’s top clinical microbiology meeting

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Jenny Bryan

Medical Writer

London
UK

 

Billed as the largest and most important ­meeting in the field of clinical microbiology and infections ever seen in Europe, ECCMID-ICC was the first joint conference of its organising societies, the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and the International Society of Chemotherapy (ISC). The programme included keynote lectures, symposia, meet-the-expert sessions, educational workshops, poster sessions and additional meetings of the study and working groups of both societies.

Leukaemia guidelines on prophylaxis
Antifungal prophylaxis should be a routine part of supportive care for leukaemia patients undergoing chemotherapy and for other cancer patients who require allogeneic haematopoietic stem cell transplantation (HSCT), according to European guidelines just produced by the 1st European Conference on Infections in Leukaemia (ECIL).

For induction chemotherapy of acute leukaemia, the guidelines give the strongest recommendation (level AI) to the antifungal agent posaconazole 200 mg TID, with level CI recommendations for ­fluconazole 50–400 mg QD and itraconazole 2.5 mg/kg BID.

For allogeneic HSCT, ECIL has made AI ­recommendations for posaconazole 200 mg TID and ­fluconazole 400 mg QD, and a BI recommendation for itraconazole 200 mg BID. Micafungin 50 mg QD received a CI recommendation.

Presenting the guidelines, Dr Johan ­Maertens (Head of Clinical Haematology, Gasthuisberg ­University Hospital, Leuven, Belgium) explained that while prophylactic antifungal treatment was already widely used in leukaemia and HSCT patients, ­evidence-based recommendations were needed for the most appropriate agents.

“Almost 60 clinical trials with over 7,000 patients had been carried out, but solid scientific conclusions were not available because of the variation in design, power and endpoints of the studies. There were also new agents which needed to be considered,” said Dr Maertens.

He added that the decision to prioritise ­posaconazole for antifungal prophylaxis was based on the recent publication of two large clinical trials which demonstrated the benefits of the drug in preventing invasive aspergillosis and reducing mortality related to invasive fungal infections.(1,2)

In one of the studies in more than 600 patients with acute myelogenous leukaemia (AML) or myelo‑

dysplastic syndromes (MDS), posaconazole also ­significantly reduced overall mortality compared with either fluconazole or itraconazole (p = 0.04).(2)

The lead investigator of the study, Dr Oliver ­Cornely (Department of Internal Medicine, ­University of Cologne, Germany) pointed out: “This is the first large well-controlled study in this setting which has shown a reduction in overall mortality.”

He added that the study showed that the number needed to treat (NNT) for posaconazole to prevent a fungal infection in neutropenic patients was 14 – low enough for physicians to see benefits in their practices.

Dr Cornely also reported data from his own unit in Cologne which showed a reduction in probable or proven invasive fungal infection during the first induction cycle of chemotherapy, from 15% in the years 2003–5, before antifungal prophylaxis was introduced, to only 3% – just one patient – in 2006, following the introduction of posaconazole prophylaxis for AML patients.

Empirical or pre-emptive therapy?
Pre-emptive antifungal therapy based on early diagnostic evidence of fungal invasion could reduce the need for empirical treatment in some cancer and other high-risk patients. But, as Professor John Perfect (Department of Molecular Genetics and Microbiology, Duke University Medical Centre, ­Durham, USA) pointed out at a symposium sponsored by Schering-Plough/Essex Pharma, few ­centres are routinely using tests to detect fungal infections before the onset of clinical symptoms, owing to doubts about the accuracy and/or interpretation of results and expense.

Professor Perfect suggested that, when combined with CT scans for infiltrates, detection of the Aspergillus galactomannan antigen can be very effective in determining the need for pre-emptive therapy. He described a screening study of these techniques which showed that it was possible to reduce empirical antifungal use from 35% to 7.7% of treatment episodes, with an accompanying 63.6% survival rate for patients with invasive fungal infection (IFI).(3) This approach also led to early initiation of antifungal therapy in 10 episodes where ­fungal infection was not suspected. Only one case of fungal infection – a patient with zygomycosis – was missed.

However, as Professor Perfect pointed out, there are only a few dozen hospitals where galactomannan

testing is available, and even in these units it is greatly underused. He said other tests – such as β-D-glucan, which can detect infection 4–8 days before culture tests, and fungal DNA detection by polymerase chain reaction (PCR) techniques – are also promising but are not yet ready for routine
practice.

Professor Perfect stressed that, in the meantime, it is essential that hospitals become more aware of their own fungal epidemiology and define high-risk groups most in need of prophylaxis (eg, ­leukaemia patients undergoing chemotherapy; bone marrow, lung, pancreas and small-bowel transplant patient; neonates; and AIDS and ICU patients). He added that any analysis of the costs of antifungal ­prophylaxis should take into account not only the drug acquisition costs but also the hospitalisation costs for patients with IFIs, currently estimated at more than $82,000 per case for invasive ­aspergillosis and $34,000–$44,500 per patient for invasive candidiasis.

Could combination therapy aid outcomes?
Combining azoles or liposomal amphotericin B with echinocandins, or boosting the effects of conventional antifungal therapies with cytokines or novel antibodies, were proposed as possible new ways of improving future outcomes for patients with IFIs.

Speaking at a Gilead-sponsored symposium,
Dr Luis Ostrosky-Zeichner (University of Texas, Houston, USA) described the results of the recent Combistrat Trial which reported that, at week 12, 80% of 15 immunocompromised patients with invasive aspergillosis treated with standard doses of liposomal amphotericin B (3 mg/kg/day) and ­caspofungin had a favourable response, compared with 67% of 15 patients who had high-dose ­liposomal ­amphotericin B (10 mg/kg/day).

Dr Ostrosky-Zeichner told delegates this was the first prospective randomised trial of combination ­versus single-agent therapy for invasive aspergillosis, and it will now be followed up with a larger study to try to confirm the results.

At the Novartis-sponsored symposium on biological treatments for fungal infections, ­Professor ­Malcolm Richardson (University of Helsinki, ­Finland) explained that combining antifungal agents with different modes of action and ranges of ­activity offers the potential to improve antifungal efficacy, shorten duration of therapy, lower drug-related ­toxicities and reduce the risk of resistance.

In this context, Professor Peter Pappas (Division of Infectious Diseases, University of ­Alabama, Birmingham, USA) described in vivo and in vitro studies demonstrating the additive effects of granulocyte-macrophage colony stimulating ­factor (GM-CSF) on antifungal agents, but expressed ­concerns that the cytokine could aggravate the inflammatory response. He said interferon-gamma has demonstrated synergy with antifungals in vivo and in vitro, but data relating to use of these combinations against human fungal infections are limited.

Reporting the latest findings with the anticandidal heat shock protein (HSP 90) antibody ­fragment efungumab, Professor James Burnie (Department of Medical Microbiology, Manchester University, UK) said early superiority of the combination of liposomal amphotericin B and ­efungumab had been shown compared with liposomal ­amphotericin B
alone in treating invasive candidiasis.4 Of 56 patients in the combination treatment group, 84% achieved a complete (clinical and ­mycological) response, compared to 48% of 61 patients in the ­amphotericin B group (p < 0.001). Candida ­mortality at day 33 was 4% with combination treatment, compared with 18% with amphotericin B, and three-month overall survival for the two treatments was the same, at 48%.

Professor Burnie explained that for the future, it would be important to identify patients most likely to benefit from the combined antibody/antifungal drug treatment, possibly based on their HLA and Toll-like receptor (TLR) haplotypes. NeuTec Pharma – the company which developed efungumab – has been acquired by Novartis and, in response to ­delegates’ questions, Professor Burnie predicted that issues related to the manufacture of the antibody raised by the European Medicines Agency (EMEA) would now be resolved.

Emerging groups at risk of infection
Rheumatoid arthritis and colitis patients are among new groups who may be at risk of fungal infection, as a result of treatment with the new generation of immunomodulatory agents, such as the anti-TNF antibodies infliximab and etanercept.

In a wide-ranging review, Dr Patricia Muñoz
(Clinical Microbiology and Infectious Diseases Service, Hospital General Universitario Gregorio Marañón, Madrid, Spain) reported FDA data (1998–2002) showing a fungal infection rate of 239/100,000 with infliximab and 70/100,000 with etanercept. She explained that the higher rate and earlier onset of infection with infliximab (typically after about 40 days of treatment compared to 236 days) was thought to be due to the more complete binding of the antibody to the cytokine.

Dr Muñoz also described the different ­profiles of the monoclonal antibodies rituximab and ­alemtuzumab, which cause lysis of B lymphocytes and are licensed for lymphoma treatment. While rituximab appears to be associated mainly with viral infection, a significant proportion of ­serious ­fungal infections has been reported with ­alemtuzumab.

Dr Muñoz explained that growing evidence ­suggests that patients treated with ­alemtuzumab to combat transplant rejection are most at risk of fungal infection and she suggested that antifungal prophylaxis be considered for these patients and for those requiring alemtuzumab for long-term cancer treatment of two years’ duration and more.

Asthma: a new treatment indication?
Antifungal treatment may have a role in treating asthma, according to data from the FAST study presented by Professor David Denning (­Wythenshawe Hospital, Manchester, UK) in his keynote lecture on new clinical and molecular targets for antifungal therapy.

He said patients with severe asthma and proven fungal sensitivity scored significantly better on the well-respected Asthma Quality of Life Questionnaire (AQLQ) after eight months’ treatment with ­itraconazole, in addition to their usual medication, than placebo (p = 0.014). Professor Denning explained that the 0.82 improvement in AQLQ score achieved with itraconazole was well above the 0.5 threshold generally agreed to have clinical significance, and was higher than the 0.4 improvement seen with omalizumab, the recently introduced novel antibody treatment for severe asthma.

References
1. Ullmann AJ, Lipton JH, Vesole DH, et al.
Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. N Engl J Med 2007;356:335-47.
2. Cornely OA, Maertens J, Winston DJ, et al. Posaconazole vs fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med 2007;356:348-59.
3. Maertens J, Theunissen K, Verhoef G, et al. Galactomannan and computed tomography-based pre-emptive antifungal therapy in neutropenic patients at high risk for invasive fungal infection: a prospective feasibility study. Clin Infect Dis 2005;1;41(9):1242-50.
4. Pachl J, Svoboda P, Jacobs F, et al. A randomized, blinded, multicenter trial of lipid-associated amphotericin B alone versus in combination with an antibody-based inhibitor of heat shock protein 90 in patients with invasive candidiasis. Clin Infect Dis 2006;15;42(10):1404-13.



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