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Over 8,000 clinicians and scientists attended this year’s ECCMID in Finland to discuss in detail the issues surrounding fungal infections
Jenny Bryan
Changing patterns of microbial incidence and resistance, increasingly effective targeting of prophylaxis strategies, and growing awareness of patient variation in therapeutic drug levels were important themes running through extensive presentations on fungal infection at this year’s meeting of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID), attended by more than 8,000 clinicians and scientists.
Trends in candidaemia and aspergillosis
Increasing emergence of non-albicans strains of Candida infection was reported from centres in Europe and Australia. Dr Cornelia Lass-Florl, from Innsbruck Medical University, Innsbruck, Austria, drew attention to a recent report from the AmarCand Study Group in France which showed that non-albicans species were responsible for nearly half of Candida cases in the Intensive Care Unit (ICU), with high levels of resistance to fluconazole in patients who had previously been treated with the drug, especially in those with Candida glabrata and C parapsilosis.[1]
Dr Elliott Playford, from Princess Alexandra Hospital, Brisbane, Australia, reported a fourfold increase in incidence of candidaemia in Queensland hospitals between 1999 and 2008, with a notable rise occurring in medical and surgical wards. While C albicans levels had fallen, there had been a significant increase in C parapsilosis. Dr Playford concluded that the increased burden of infection outside the ICU, especially in heterogeneous groups of patients in general wards, was particularly challenging for effective identification and appropriate treatment.
Dr Olivier Lortholary, from the Institut Pasteur, Paris, France, demonstrated the value of establishing a national surveillance network, with standardised reporting criteria, to monitor changes in prevalence of invasive aspergillosis (IA) and response to treatment. He presented data collected from four regions of France, between 2005 and 2007, which showed a median incidence of IA of 0.223 per 1,000 admissions, with 80% of cases in haematological malignancies, but a small shift away from leukaemia towards lymphoproliferative diseases as major risk factors. Eighty five percent of infections were caused by Aspergillus fumigatus, and first-line therapy was voriconazole in 49% of cases, caspofungin in 14%, lipid formulations of amphotericin B (AMB) in 9% and combinations in 20%. Mortality at day 90 was 41% when voriconazole was used, and 60% when it was not.
Dr Lortholary explained that the network will be expanded to other parts of France, and accumulating data will enable physicians to assess the impact of new management strategies and to identify new populations at risk of infection.
Diagnosis still dependent on culture
Culture-based assays remain the standard diagnostic technique for fungal testing, if delegate responses at ECCMID were indicative of general practice. Over half of delegates attending an educational workshop, organised by the ESCMID Fungal Infection Study Group, said they still relied mainly on cultures and microscopic examinations, compared with 18% who relied on fungal antigens, 10% on secreted fungal molecules and 15% on nucleic acid tests.
In a review of recently reported studies of culture tests, Dr Lass-Florl pointed to the importance of using anaerobic cultures for identifying C glabrata following recent data showing that the organism grows much faster in anaerobic than aerobic conditions. In one such study, 23% of C glabrata isolates were detected only by anaerobic culture tests.[2]
To make best use of the galactomannan (GM) assay, Dr Lass-Florl pointed to the good results achieved for IA and broncheoalveolar lavage fluid in lung transplant and non-neutropenic patients.
A cut-off threshold of 0.5 yielded sensitivity and specificity results of 82% and 96% in lung transplant patients[3] and 88% and 87% respectively in non-neutropenic patients.[4] Another recent study showed that serial monitoring of GM (2-3 times per week) enabled diagnosis to be made around a week earlier than with conventional means, and correlated with survival in neutropenic patients.[5]
Serial testing using (1,3) beta-D-glucan assays also aids diagnostic accuracy. Dr Lass-Florl reported results showing that persistently raised glucan levels (>3 samples above a cut-off of 40 pg/ml) were predictive of IFI in long-term ICU patients.[6]
Many PCR tests, no instant winner
Preliminary results from the European Aspergillus Polymerase Chain Reaction Initiative (EAPCRI), which is trialling 12 different types of test at 69 centres in 24 countries, suggest that it is not the PCR platform that matters, but who is using it and how the test is carried out. Dr Peter Donnelly, from Nijmegen University Centre for Infectious Diseases, Nijmegen, the Netherlands, explained that some investigators are consistently achieving better results than others, with higher specificity and sensitivity, but they are all using different platforms. The next step is to explore the technical factors, such as sample numbers, blood treatment, lysis of fungal cells and purification of fungal DNA, which are most important for achieving the best results. Dr Donnelly described research that has already shown different predictive requirements for PCR tests depending on whether they are being used for IFI screening or to confirm diagnosis. For screening, in a situation where the prevalence of infection is low, a PCR test with a high sensitivity is needed to ensure a low number of false negatives. But, for a diagnostic test, where the prevalence is likely to be high, a high specificity test is needed to ensure a low number of false positives. He concluded that PCR testing can indicate the presence of infection before there is evidenceof infection, especially if it is combined with galactomannan testing.
Neutropenia predicts aspergillosis mortality
Resolution of neutropenia proved more important than choice of antifungal therapy, in a survey conducted at 21 Italian haematology centres between 2004 and 2007. Presenting the results on behalf of the SEIFEM group, Dr Livio Pagano reported results of 140 cases of IA in AML patients, 61% of which occurred after the first course of chemotherapy. Overall attributable mortality was 27%, with outcome significantly influenced by AML phase (p < 0.001), duration of neutropenia
(p = 0.05) and recovery from neutropenia (p < 0.001). Systemic antifungal prophylaxis was administered to 101 patients, itraconazole to 68 patients and fluconazole to 33 patients. Mortality was 20.5% in those who had no prophylaxis, compared with 30% in those where it was administered (p = 0.27). No antifungal agent used for empirical or first-line therapy proved more effective than any other, nor was there any advantage of combination therapy. Dr Pagano concluded that, while the data supported the use of timely diagnostic workup and use of antifungal therapy in modifying the course of IA, none of the new drugs emerged as the most efficacious in the current series.
Careful prophylaxis targeting yields results
Careful targeting of cancer patients for antifungal prophylaxis with posaconazole, in line with recent US and European guidelines, has shown that results achieved in a typical hospital setting can be at least as good as those reported in clinical trials.
After changing IFI prophylaxis to posaconazole in acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) patients, Dr Oliver Cornely and colleagues at the University Hospital of Cologne, Germany, found that they needed to treat half the number of patients to prevent a proven or probable IFI compared with that seen in clinical trials.
Dr Cornely reported that only eight patients with febrile neutropenia needed to be treated with posaconazole 200 mg tid, instead of previous prophylactic regimens, to prevent one case of proven or probable IFI. This compared with a number needed to treat (NNT) of 16 patients in the clinical trial of posaconazole prophylaxis,[7] which provided key evidence for prophylaxis recommendations in the recent Infectious Diseases Society of America (IDSA) and European Conference on Infections in Leukaemia (ECIL) guidelines.[8,9]
Patients targeted for posaconazole prophylaxis had neutropenia for more than 10 days, and a fever lasting more than 72 hours, or a positive galactomannan test, but no evidence of lung infiltrates on CT scanning. Posaconazole prophylaxis was also effective in preventing infiltrates, with an NNT of 3.7.
For both infiltrate and infection prevention, posaconazole prophylaxis was significantly more effective than the previous regimen (p = 0.0002 and p = 0.014 respectively).
Can therapeutic drug monitoring improve azole effectiveness?
Considerable debate surrounds the potential for therapeutic
drug monitoring (TDM) to ensure all patients get full benefit from azole treatment of fungal infection. In a review of the differing pharmacokinetics and pharmacodynamics of this group of drugs, Dr William Hope, from the University of Manchester, Manchester, UK, gave strong support to TDM, especially when itraconazole and voriconazole, which have nonlinear pharmacokinetics, are used. He presented studies of itraconazole which showed that, in order to balance safety and efficacy, a steady-state trough concentration of >0.5 mg/l (HPLC) is needed, and a concentration of >5 mg/l and <17.1 mg/l if a bioassay system is used. In patients found to have low itraconazole levels with standard dosing, Dr Hope recommended that the itraconazole dose should be increased from 200 mg bd to 300 mg bd.
[[HPE45.22]]
For voriconazole the therapeutic range appears to lie between 1 mg/l and 5–6 mg/l, with concentrations above this level associated with risk of CNS and hepatic toxicity. But Dr Hope pointed out that there is very high between-patient variability in voriconazole levels, which is partially dependent on CYP2C19 status, with extensive metabolisers registering low voriconazole levels, and the reverse in low metabolisers. Dr Hope recommended IV loading for voriconazole, and dose escalation from 200 mg bd to 300 mg bd, in order to achieve therapeutic targets.
Dr Hope told delegates that there is accumulating evidence to support TDM in posaconazole too. He presented data showing a progressively higher rate of response with increasing posaconazole levels and suggested that a level of 0.7 mg/l is needed for prophylaxis and 1.5 mg/l for established infection. He concluded that a fractionated dose may enhance drug exposure, but added that patients may not get additional benefit from a dose >800 mg per day.
References
1. Leroy O, Gangneux J-P, Montravers P, et al. Epidemiology, management, and risk factors for death of invasive Candida infections in critical care: a multicenter, prospective, observational study in France (2005–2006). Crit Care Med
2009 May;37(5):1612-8.
2. Hui M, Ho W-H, Lam W-H. Candida glabrata fungaemia:
the importance of anaerobic blood culture. J Med Microbiol 2009;58:396-7.
3. Husain S, Paterson DL, Studer SM, et al. Aspergillus galactomannan antigen in the bronchoalveolar lavage fluid for the diagnosis of invasive aspergillosis in lung transplant recipients. Transplantation 2007 May 27;83(10):1330-6.
4. Meersseman W, Lagrou K, Maertens J, et al. Galactomannan in bronchoalveolar lavage fluid: a tool for diagnosing aspergillosis in intensive care unit patients. Am J Respir Crit Care Med 2008 Jan 1;177(1):27-34.
5. Maertens J, Buvé K, Theunissen K, et al. Galactomannan serves as a surrogate endpoint for outcome of pulmonary invasive aspergillosis in neutropenic hematology patients. Cancer 2009 Jan 15;115(2):355-62.
6. Presterl E, Parschalk B, Bauer E, et al. Invasive fungal infections and (1,3)-beta-d-glucan serum concentrations in long-term intensive care patients. Int J Infect Dis 2009 Jan 19. [Epub ahead of print].
7. Cornely OA, Maertens J, Winston DJ, et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med 2007;356(4):348-59.
8. Walsh TJ, Anaissie EJ, Denning DW, et al. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis 2008; 46:327-60.
9. Guidelines from the First European Conference on Infections in Leukaemia: ECIL 1. Eur J Cancer 2007; 5 Suppl:1-59.
