- Email: [email protected]
Up to date epidemiology, diagnosis and management of invasive fungal infections
EDITORIAL
10.1111/1469-0691.12642
Up to date epidemiology, diagnosis and management of invasive fungal infections I. Oren and M. Paul Infectious Diseases Institute, Rambam Health Care Campus, Bruce Rappaport Faculty of Medicine, Technion – Israely Institute of Technology, Haifa, Israel E-mail: [email protected]
This issue of Clinical Microbiology and Infection is dedicated to invasive fungal infections (IFI) based on the ESCMID conference held in Rome on January 2013. The reviews summarize the progress achieved in the fields of epidemiology, diagnosis and management of Candida, Aspergillus and Mucor invasive infections.
Epidemiology Candida spp. have become important causes of sepsis in hospitals with incidence constantly growing over the last 20 years. Candida spp. is now the 4th most common isolate of bloodstream infections in many countries (and the most common IFI), mainly due to the increasing complexity of medical care [1]. Candida albicans is still the main cause of candidemia in population-based studies worldwide, but its relative frequency is decreasing, while the frequency of the other species is increasing. Patients’ characteristics influence Candida species distribution; C. glabrata infections are more common in the elderly, C. krusei in immunocompromised patients, while C. parapsilosis is most common in children and neonates. Risk factors for candidemia include neutropenia, especially during periods of mucositis, broad spectrum antibiotic therapy, abdominal surgery mainly involving the colon, total parenteral nutrition and combination of such risk factors. Invasive aspergillosis is the second most common IFI, with increasing incidence over the last 20 years along with the advances in the treatment of hematological malignancies. Prolonged neutropenia is the main risk factor. Patients with acute myeloid leukaemia (AML) and those who undergo allogeneic hematopoietic stem cell transplantation (HSCT) have prolonged durations (more than 10 days) of neutropenia and are at highest risk. In the highest risk group, invasive aspergillosis rates can reach 25% [2]. An optimal risk score for invasive aspergillosis would have to include fine details on the underlying malignancy and its predicted response to chemotherapy, chemotherapy regimens, allogeneic transplantation
and the presence of GVHD. However, the incidence of invasive aspergillosis is very much dependent on local epidemiology and the quality of air control in hemato-oncological units. Thus, in some settings, invasive aspergillosis is more frequent than invasive candidiasis [2]. Mucormycosis is the second most common invasive mould infection and its incidence increased from 0.7 per million in 1997 to 1.2 per million in 2006 [3]. In addition to immunesuppression, there are some unique host risk factors for mucormycosis such as diabetes keto-acidosis, burns, iron overload and, on the other hand, deferoxamine therapy. The specific clinical syndrome of mucormycosis is associated with host risk factors; thus, pulmonary mucormycosis is more common in patients with hematological malignancies, while rhino-cerebral mucormycosis is more common in diabetic patients [4]. The aetiologic agents involved in the disease have been reclassified in recent years, based on molecular methods establishing taxonomy [4]. Thus, “zygomycosis” was reclassified to either “mucormycosis” or “entomophthoromycosis”. It appears that genera that belong to the subphylum mucormycotina are ubiquitous worldwide and cause severe life-threatening infections in immunocompromised patients, while entomophthoromycotina are found in tropical regions and cause chronic subcutaneous infections in otherwise healthy patients. Early identification of mucor spp. to the species level and advances in epidemiological data will perhaps allow in the future better prediction of patients’ prognosis and tailoring of treatment.
Diagnostics Traditional microbiological tests are not sensitive enough for the diagnosis of fungal infections. It has been shown that blood cultures may fail to diagnose candidemia in up to 50% of the cases [5]. In mould infections, the sensitivity of culture is even lower. This led to the development of noncultural serological and molecular tests, for the diagnosis of invasive fungal disease. Of the serological tests, the galactomannan antigen for
ª2014 The Authors Clinical Microbiology and Infection ª2014 European Society of Clinical Microbiology and Infectious Diseases
2
Clinical Microbiology and Infection, Volume 20 Supplement 6, June 2014
aspergillus and 1-3 beta-D-glucan for fungal infections other than cryptococcosis and zygomycoses are included in the diagnostic criteria for IFI [6]. Galactomannan detection in the BAL fluid has higher sensitivity and specificity for diagnosing invasive pulmonary aspergillosis than serum [7]. PCR-based tests have not reached the same level of acceptance, mainly due to lack of standardization in the type of clinical sample (serum, plasma, tissue), primer selection (“pan-fungal”, species specific) and PCR format (qualitative vs. quantitative, real time) [8]. Systematic reviews support the diagnostic potential of such tests. Thus, using acceptable diagnostic criteria (other than PCR), systematic reviews have summarized that PCR in blood had a sensitivity of 0.88 (95% CI 0.75–0.94) for diagnosis of IA if a single positive sample was required to define positivity and a specificity 0.87 (95% CI 0.78–0.93) if two positive samples defined test positivity [9]; PCR in bronchoalveolar lavage had a sensitivity and specificity of 0.91 (95% CI 0.79–0.96) and 0.92 (95% CI 0.87–0.96), respectively, for the diagnosis of invasive pulmonary aspergillosis [10]; and PCR in blood had a sensitivity of 0.95 (95% CI 0.88–0.98) and specificity of 0.92 (95% CI 0.88–0.95) among patients at risk of diagnosis of invasive candidiasis [11]. Variability in PCR methods was responsible for some of the heterogeneity in the meta-analyses, but the ability of systematic reviews to identify optimal PCR techniques is limited by the multitude of method components and their interactions. Defining a standard methodology should be performed basing the summary of diagnostic study findings but also relying on expert opinion. The future will probably see the incorporation of molecular tests in diagnostic algorithms and criteria.
Prophylaxis Antifungal prophylaxis has been shown to reduce mortality among high-risk hemato-oncological patients [12]. A recent network meta-analysis of RCTs [13], including direct and indirect comparisons, summarized that fluconazole, itraconazole solution, voriconazole, posaconazole, low dose liposomal amphotericin B and micafungin have the potential to significantly reduce total IFI rates (compared with no treatment). Posaconazole and voriconazole have been estimated as more effective than fluconazole and itraconazole capsules (that are poorly absorbed) with regard to IFIs with more data supporting posaconazole. Itraconazole oral suspension has better bioavailability than capsules, but poor gastrointestinal tolerability hampers its widespread use. Universal adoption of posaconazole is hindered by the nonavailability of an IV formulation until now for patients who cannot take oral treatment during periods of severe
CMI
mucositis (only recently approved [14]), costs and concerns regarding resistance induction and the lack of treatment options for breakthrough infections. Indeed, the downside of any prophylaxis is its potential to increase infections caused by resistant strains. Thus, posaconazole and itraconazole have been associated with the appearance of C. glabrata with decreased azole susceptibility and fluconazole was associated with the appearance of C. glabrata and C. krusei [15]. Voriconazole, itraconazole and caspofungin have been associated with appearance of Mucor spp. infections [16,17]. Centres need to define local protocols for antifungal prophylaxis based on their local epidemiology of candidemias and incidence of invasive aspergillosis. The rates of invasive aspergillosis without antimould prophylaxis in recent RCTs of posaconazole and voriconazole averaged 7–8% of patients at 100 days. Thus, evidence is relevant for settings with similar incidence. Although RCTs have focused on the main patient populations, that is, AML induction, allogeneic transplantation with GVHD, prophylaxis might need to be extended to other patients, not specifically examined in RCTs, based on their risk of IFIs.
Pre-emptive vs. Empirical Treatment In 1982, Pizzo et al. showed that empirical antifungal therapy with amphotericin B in patients with cancer with prolonged fever with granulocytopenia reduce the number of IFIs and fungal deaths [18]. This practice soon became part of the guidelines for management of febrile neutropenic patients. With the development of modern imaging and serological/ molecular markers, which allow early detection of IFI, the “pre-emptive” strategy became optional, where IFIs are actively searched for and antifungal treatment is started when there is an indication of IFI other than fever (“diagnostic driven” strategy) [19]. The rationale for pre-emptive treatment is to decrease treatment-related toxicity, costs and resistance emergence and perhaps to improve patient outcomes through more tailored treatment. Currently published RCTs show that the pre-emptive strategy is not necessarily associated with reduced antifungal use (although in 2/3 studies it was) and usually leads to the diagnosis of more IFIs [20–22]. All-cause mortality was not significantly affected in the three trials, although only one trial was designed to examine survival [20]. Compiling or comparing between these studies is difficult because the diagnostic and management pathways of empirical and pre-emptive strategies were heterogeneous. Thus, the debate regarding empirical vs. pre-emptive treatment is open, with a trend favouring the more tailored preemptive strategy in an attempt to improve patients’ manage-
ª2014 The Authors Clinical Microbiology and Infection ª2014 European Society of Clinical Microbiology and Infectious Diseases, CMI, 20 (Suppl. 6), 1–4
CMI
3
ment [23]. With effective antimould prophylaxis, the question is less relevant.
Treatment of Established Infections The advances regarding the antifungal armamentarium to treat IFIs are described in this issue. Significant advance has also been made in standardizing susceptibility testing. The EUCAST and CLSI have developed breakpoints that are now established to interpret susceptibility results for amphotericin, azoles and echinocandins for most Candida spp. These documents are available online and permit clinicians better interpretation and selection of antifungals. With Aspergillus spp., MIC values do not always directly associate with response to antifungal therapy and work is in progress. Despite these advances, mortality rates of IFIs remain unacceptably high, especially among immunocompromised patients. Mucormycosis is more difficult to cure than other mycosis and carries mortality rates of 40–70% in the immunocompromised host despite treatment. This is attributed to extensive angioinvasion, increased virulence, difficulties in early diagnosis lacking a serological test, nonspecific clinical manifestations and the limitations of antifungal therapy [4,24]. As with all anti-infective treatment, stewardship programmes for judicious prescription are necessary for antifungals [25]. Unique to the treatment of infections is the issue of resistance induction or shift toward resistant strains following treatment. Thus, stewardship programmes must promote optimal antifungal treatment on the one hand, but restrict redundant and unnecessary antifungal use on the other hand. Of all antimicrobials, economic considerations apply most to antifungals, because of the limited number of drugs available and the significant costs of new drugs. These considerations must also be uniquely addressed in antifungal stewardship programmes. In summary, significant advance has been achieved in the diagnosis and management of IFIs summarized in the current theme issue and recently published guidelines [26,27]. For a complete list of ESCMID guidelines on IFIs please see: https:// www.escmid.org/escmid_library/medical_guidelines/escmid_ guidelines/. These come in response to increasing incidence of fungal infections in hospitals associated with increasing complexity of the patient case mix and more treatment options for patients with cancer. Obtaining unbiased evidence for management decisions is critical.
Transparency Declaration The authors declare no conflict of interests.
References 1. Guinea J. Global trends in the distribution of Candida species causing candidemia. Clin Microbiol Infect 2014; 20 (suppl): 5–10. 2. Pagano L, Caira M, Candoni A et al. The epidemiology of fungal infections in patients with hematologic malignancies: the SEIFEM-2004 study. Haematol 2006; 91: 1068–1075. 3. Petrikkos G, Skiada A, Drogari-Apiranthitou M. Epidemiology of mucormycosis in Europe. Clin Microbiol Infect 2014; 20(suppl): 52–58. 4. Katragkou A, Walsh TJ, Roilides E. Why is mucormycosis more difficult to cure than more common mycoses? Clin Microbiol Infect 2014; 20 (suppl): 74–81. 5. Clancy CJ, Nguyen MH. Finding the “missing 50%” of invasive candidiasis: how nonculture diagnostics will improve understanding of disease spectrum and transform patient care. Clin Infect Dis 2013; 56: 1284–1292. 6. De Pauw B, Walsh TJ, Donnelly JP et al. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis 2008; 46: 1813–1821. 7. Zou M, Tang L, Zhao S et al. Systematic review and meta-analysis of detecting galactomannan in bronchoalveolar lavage fluid for diagnosing invasive aspergillosis. PLoS One 2012; 7: e43347. 8. Alanio A, Bretagne S. Difficulties with molecular diagnostic tests for mold and yeast infections: where do we stand? Clin Microbiol Infect 2014; 20 (suppl): 36–41. 9. Mengoli C, Cruciani M, Barnes RA, Loeffler J, Donnelly JP. Use of PCR for diagnosis of invasive aspergillosis: systematic review and metaanalysis. Lancet Infect Dis 2009; 9: 89–96. 10. Sun W, Wang K, Gao W et al. Evaluation of PCR on bronchoalveolar lavage fluid for diagnosis of invasive aspergillosis: a bivariate metaanalysis and systematic review. PLoS One 2011; 6: e28467. 11. Avni T, Leibovici L, Paul M. PCR diagnosis of invasive candidiasis: systematic review and meta-analysis. J Clin Microbiol 2011; 49: 665–670. 12. Robenshtok E, Gafter-Gvili A, Goldberg E et al. Antifungal prophylaxis in cancer patients after chemotherapy or hematopoietic stem-cell transplantation: systematic review and meta-analysis. J Clin Oncol 2007; 25: 5471–5489. 13. Pechlivanoglou P, Le HH, Daenen S, Snowden JA, Postma MJ. Mixed treatment comparison of prophylaxis against invasive fungal infections in neutropenic patients receiving therapy for haematological malignancies: a systematic review. J Antimicrob Chemother 2014; 69: 1–11. 14. http://www.mercknewsroom.com/news-release/prescription-medicinenews/fda-approves-mercks-noxafil-posaconazole-injection-18-mgml-i (Accessed April 2014). 15. Mann PA, McNicholas PM, Chau AS et al. Impact of antifungal prophylaxis on colonization and azole susceptibility of Candida species. Antimicrob Agents Chemother 2009; 53: 5026–5034. 16. Imhof A, Balajee SA, Fredricks DN, Englund JA, Marr KA. Breakthrough fungal infections in stem cell transplant recipients receiving voriconazole. Clin Infect Dis 2004; 39: 743–746. 17. Pang KA, Godet C, Fekkar A et al. Breakthrough invasive mould infections in patients treated with caspofungin. J Infect 2012; 64: 424–429. 18. Pizzo PA, Robichaud KJ, Gill FA, Witebsky FG. Empiric antibiotic and antifungal therapy for cancer patients with prolonged fever and granulocytopenia. Am J Med 1982; 72: 101–111. 19. Cordonnier C, Robin C, Alanio A, Bretagne S. Antifungal pre-emptive strategy for high-risk neutropenic patients: why the story is still ongoing. Clin Microbiol Infect 2014; 20 (suppl): 27–35.
ª2014 The Authors Clinical Microbiology and Infection ª2014 European Society of Clinical Microbiology and Infectious Diseases, CMI, 20 (Suppl. 6), 1–4
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Clinical Microbiology and Infection, Volume 20 Supplement 6, June 2014
20. Cordonnier C, Pautas C, Maury S et al. Empirical versus preemptive antifungal therapy for high-risk, febrile, neutropenic patients: a randomized, controlled trial. Clin Infect Dis 2009; 48: 1042–1051. 21. Morrissey CO, Chen SC, Sorrell TC et al. Galactomannan and PCR versus culture and histology for directing use of antifungal treatment for invasive aspergillosis in high-risk haematology patients: a randomised controlled trial. Lancet Infect Dis 2013; 13: 519–528. 22. Hebart H, Klingspor L, Klingebiel T et al. A prospective randomized controlled trial comparing PCR-based and empirical treatment with liposomal amphotericin B in patients after allo-SCT. Bone Marrow Transplant 2009; 43: 553–561. 23. Donnelly JP, Maertens J. The end of the road for empirical antifungal treatment? Lancet Infect Dis 2013; 13: 470–472.
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24. Binder U, Maurer E, Lass-Fl€ orl C. Mucormycosis - from the pathogens to the disease. Clin Microbiol Infect 2014; 20 (suppl): 60–66. 25. Ruhnke M. Antifungal stewardship in invasive Candida infections. Clin Microbiol Infect 2014; 20 (suppl): 11–18. 26. Cornely OA, Cuenca-Estrella M, Meis JF et al. European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Fungal Infection Study Group (EFISG) and European Confederation of Medical Mycology (ECMM) 2013 joint guidelines on diagnosis and management of rare and emerging fungal diseases. Clin Microbiol Infect 2014; 20 (Suppl): 1–4. 27. Ullmann AJ, Akova M, Herbrecht R et al. ESCMID* guideline for the diagnosis and management of Candida diseases 2012: adults with haematological malignancies and after haematopoietic stem cell transplantation (HCT). Clin Microbiol Infect 2012; 18 (Suppl): 53–67.
ª2014 The Authors Clinical Microbiology and Infection ª2014 European Society of Clinical Microbiology and Infectious Diseases, CMI, 20 (Suppl. 6), 1–4
10.1111/1469-0691.12642
Up to date epidemiology, diagnosis and management of invasive fungal infections I. Oren and M. Paul Infectious Diseases Institute, Rambam Health Care Campus, Bruce Rappaport Faculty of Medicine, Technion – Israely Institute of Technology, Haifa, Israel E-mail: [email protected]
This issue of Clinical Microbiology and Infection is dedicated to invasive fungal infections (IFI) based on the ESCMID conference held in Rome on January 2013. The reviews summarize the progress achieved in the fields of epidemiology, diagnosis and management of Candida, Aspergillus and Mucor invasive infections.
Epidemiology Candida spp. have become important causes of sepsis in hospitals with incidence constantly growing over the last 20 years. Candida spp. is now the 4th most common isolate of bloodstream infections in many countries (and the most common IFI), mainly due to the increasing complexity of medical care [1]. Candida albicans is still the main cause of candidemia in population-based studies worldwide, but its relative frequency is decreasing, while the frequency of the other species is increasing. Patients’ characteristics influence Candida species distribution; C. glabrata infections are more common in the elderly, C. krusei in immunocompromised patients, while C. parapsilosis is most common in children and neonates. Risk factors for candidemia include neutropenia, especially during periods of mucositis, broad spectrum antibiotic therapy, abdominal surgery mainly involving the colon, total parenteral nutrition and combination of such risk factors. Invasive aspergillosis is the second most common IFI, with increasing incidence over the last 20 years along with the advances in the treatment of hematological malignancies. Prolonged neutropenia is the main risk factor. Patients with acute myeloid leukaemia (AML) and those who undergo allogeneic hematopoietic stem cell transplantation (HSCT) have prolonged durations (more than 10 days) of neutropenia and are at highest risk. In the highest risk group, invasive aspergillosis rates can reach 25% [2]. An optimal risk score for invasive aspergillosis would have to include fine details on the underlying malignancy and its predicted response to chemotherapy, chemotherapy regimens, allogeneic transplantation
and the presence of GVHD. However, the incidence of invasive aspergillosis is very much dependent on local epidemiology and the quality of air control in hemato-oncological units. Thus, in some settings, invasive aspergillosis is more frequent than invasive candidiasis [2]. Mucormycosis is the second most common invasive mould infection and its incidence increased from 0.7 per million in 1997 to 1.2 per million in 2006 [3]. In addition to immunesuppression, there are some unique host risk factors for mucormycosis such as diabetes keto-acidosis, burns, iron overload and, on the other hand, deferoxamine therapy. The specific clinical syndrome of mucormycosis is associated with host risk factors; thus, pulmonary mucormycosis is more common in patients with hematological malignancies, while rhino-cerebral mucormycosis is more common in diabetic patients [4]. The aetiologic agents involved in the disease have been reclassified in recent years, based on molecular methods establishing taxonomy [4]. Thus, “zygomycosis” was reclassified to either “mucormycosis” or “entomophthoromycosis”. It appears that genera that belong to the subphylum mucormycotina are ubiquitous worldwide and cause severe life-threatening infections in immunocompromised patients, while entomophthoromycotina are found in tropical regions and cause chronic subcutaneous infections in otherwise healthy patients. Early identification of mucor spp. to the species level and advances in epidemiological data will perhaps allow in the future better prediction of patients’ prognosis and tailoring of treatment.
Diagnostics Traditional microbiological tests are not sensitive enough for the diagnosis of fungal infections. It has been shown that blood cultures may fail to diagnose candidemia in up to 50% of the cases [5]. In mould infections, the sensitivity of culture is even lower. This led to the development of noncultural serological and molecular tests, for the diagnosis of invasive fungal disease. Of the serological tests, the galactomannan antigen for
ª2014 The Authors Clinical Microbiology and Infection ª2014 European Society of Clinical Microbiology and Infectious Diseases
2
Clinical Microbiology and Infection, Volume 20 Supplement 6, June 2014
aspergillus and 1-3 beta-D-glucan for fungal infections other than cryptococcosis and zygomycoses are included in the diagnostic criteria for IFI [6]. Galactomannan detection in the BAL fluid has higher sensitivity and specificity for diagnosing invasive pulmonary aspergillosis than serum [7]. PCR-based tests have not reached the same level of acceptance, mainly due to lack of standardization in the type of clinical sample (serum, plasma, tissue), primer selection (“pan-fungal”, species specific) and PCR format (qualitative vs. quantitative, real time) [8]. Systematic reviews support the diagnostic potential of such tests. Thus, using acceptable diagnostic criteria (other than PCR), systematic reviews have summarized that PCR in blood had a sensitivity of 0.88 (95% CI 0.75–0.94) for diagnosis of IA if a single positive sample was required to define positivity and a specificity 0.87 (95% CI 0.78–0.93) if two positive samples defined test positivity [9]; PCR in bronchoalveolar lavage had a sensitivity and specificity of 0.91 (95% CI 0.79–0.96) and 0.92 (95% CI 0.87–0.96), respectively, for the diagnosis of invasive pulmonary aspergillosis [10]; and PCR in blood had a sensitivity of 0.95 (95% CI 0.88–0.98) and specificity of 0.92 (95% CI 0.88–0.95) among patients at risk of diagnosis of invasive candidiasis [11]. Variability in PCR methods was responsible for some of the heterogeneity in the meta-analyses, but the ability of systematic reviews to identify optimal PCR techniques is limited by the multitude of method components and their interactions. Defining a standard methodology should be performed basing the summary of diagnostic study findings but also relying on expert opinion. The future will probably see the incorporation of molecular tests in diagnostic algorithms and criteria.
Prophylaxis Antifungal prophylaxis has been shown to reduce mortality among high-risk hemato-oncological patients [12]. A recent network meta-analysis of RCTs [13], including direct and indirect comparisons, summarized that fluconazole, itraconazole solution, voriconazole, posaconazole, low dose liposomal amphotericin B and micafungin have the potential to significantly reduce total IFI rates (compared with no treatment). Posaconazole and voriconazole have been estimated as more effective than fluconazole and itraconazole capsules (that are poorly absorbed) with regard to IFIs with more data supporting posaconazole. Itraconazole oral suspension has better bioavailability than capsules, but poor gastrointestinal tolerability hampers its widespread use. Universal adoption of posaconazole is hindered by the nonavailability of an IV formulation until now for patients who cannot take oral treatment during periods of severe
CMI
mucositis (only recently approved [14]), costs and concerns regarding resistance induction and the lack of treatment options for breakthrough infections. Indeed, the downside of any prophylaxis is its potential to increase infections caused by resistant strains. Thus, posaconazole and itraconazole have been associated with the appearance of C. glabrata with decreased azole susceptibility and fluconazole was associated with the appearance of C. glabrata and C. krusei [15]. Voriconazole, itraconazole and caspofungin have been associated with appearance of Mucor spp. infections [16,17]. Centres need to define local protocols for antifungal prophylaxis based on their local epidemiology of candidemias and incidence of invasive aspergillosis. The rates of invasive aspergillosis without antimould prophylaxis in recent RCTs of posaconazole and voriconazole averaged 7–8% of patients at 100 days. Thus, evidence is relevant for settings with similar incidence. Although RCTs have focused on the main patient populations, that is, AML induction, allogeneic transplantation with GVHD, prophylaxis might need to be extended to other patients, not specifically examined in RCTs, based on their risk of IFIs.
Pre-emptive vs. Empirical Treatment In 1982, Pizzo et al. showed that empirical antifungal therapy with amphotericin B in patients with cancer with prolonged fever with granulocytopenia reduce the number of IFIs and fungal deaths [18]. This practice soon became part of the guidelines for management of febrile neutropenic patients. With the development of modern imaging and serological/ molecular markers, which allow early detection of IFI, the “pre-emptive” strategy became optional, where IFIs are actively searched for and antifungal treatment is started when there is an indication of IFI other than fever (“diagnostic driven” strategy) [19]. The rationale for pre-emptive treatment is to decrease treatment-related toxicity, costs and resistance emergence and perhaps to improve patient outcomes through more tailored treatment. Currently published RCTs show that the pre-emptive strategy is not necessarily associated with reduced antifungal use (although in 2/3 studies it was) and usually leads to the diagnosis of more IFIs [20–22]. All-cause mortality was not significantly affected in the three trials, although only one trial was designed to examine survival [20]. Compiling or comparing between these studies is difficult because the diagnostic and management pathways of empirical and pre-emptive strategies were heterogeneous. Thus, the debate regarding empirical vs. pre-emptive treatment is open, with a trend favouring the more tailored preemptive strategy in an attempt to improve patients’ manage-
ª2014 The Authors Clinical Microbiology and Infection ª2014 European Society of Clinical Microbiology and Infectious Diseases, CMI, 20 (Suppl. 6), 1–4
CMI
3
ment [23]. With effective antimould prophylaxis, the question is less relevant.
Treatment of Established Infections The advances regarding the antifungal armamentarium to treat IFIs are described in this issue. Significant advance has also been made in standardizing susceptibility testing. The EUCAST and CLSI have developed breakpoints that are now established to interpret susceptibility results for amphotericin, azoles and echinocandins for most Candida spp. These documents are available online and permit clinicians better interpretation and selection of antifungals. With Aspergillus spp., MIC values do not always directly associate with response to antifungal therapy and work is in progress. Despite these advances, mortality rates of IFIs remain unacceptably high, especially among immunocompromised patients. Mucormycosis is more difficult to cure than other mycosis and carries mortality rates of 40–70% in the immunocompromised host despite treatment. This is attributed to extensive angioinvasion, increased virulence, difficulties in early diagnosis lacking a serological test, nonspecific clinical manifestations and the limitations of antifungal therapy [4,24]. As with all anti-infective treatment, stewardship programmes for judicious prescription are necessary for antifungals [25]. Unique to the treatment of infections is the issue of resistance induction or shift toward resistant strains following treatment. Thus, stewardship programmes must promote optimal antifungal treatment on the one hand, but restrict redundant and unnecessary antifungal use on the other hand. Of all antimicrobials, economic considerations apply most to antifungals, because of the limited number of drugs available and the significant costs of new drugs. These considerations must also be uniquely addressed in antifungal stewardship programmes. In summary, significant advance has been achieved in the diagnosis and management of IFIs summarized in the current theme issue and recently published guidelines [26,27]. For a complete list of ESCMID guidelines on IFIs please see: https:// www.escmid.org/escmid_library/medical_guidelines/escmid_ guidelines/. These come in response to increasing incidence of fungal infections in hospitals associated with increasing complexity of the patient case mix and more treatment options for patients with cancer. Obtaining unbiased evidence for management decisions is critical.
Transparency Declaration The authors declare no conflict of interests.
References 1. Guinea J. Global trends in the distribution of Candida species causing candidemia. Clin Microbiol Infect 2014; 20 (suppl): 5–10. 2. Pagano L, Caira M, Candoni A et al. The epidemiology of fungal infections in patients with hematologic malignancies: the SEIFEM-2004 study. Haematol 2006; 91: 1068–1075. 3. Petrikkos G, Skiada A, Drogari-Apiranthitou M. Epidemiology of mucormycosis in Europe. Clin Microbiol Infect 2014; 20(suppl): 52–58. 4. Katragkou A, Walsh TJ, Roilides E. Why is mucormycosis more difficult to cure than more common mycoses? Clin Microbiol Infect 2014; 20 (suppl): 74–81. 5. Clancy CJ, Nguyen MH. Finding the “missing 50%” of invasive candidiasis: how nonculture diagnostics will improve understanding of disease spectrum and transform patient care. Clin Infect Dis 2013; 56: 1284–1292. 6. De Pauw B, Walsh TJ, Donnelly JP et al. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis 2008; 46: 1813–1821. 7. Zou M, Tang L, Zhao S et al. Systematic review and meta-analysis of detecting galactomannan in bronchoalveolar lavage fluid for diagnosing invasive aspergillosis. PLoS One 2012; 7: e43347. 8. Alanio A, Bretagne S. Difficulties with molecular diagnostic tests for mold and yeast infections: where do we stand? Clin Microbiol Infect 2014; 20 (suppl): 36–41. 9. Mengoli C, Cruciani M, Barnes RA, Loeffler J, Donnelly JP. Use of PCR for diagnosis of invasive aspergillosis: systematic review and metaanalysis. Lancet Infect Dis 2009; 9: 89–96. 10. Sun W, Wang K, Gao W et al. Evaluation of PCR on bronchoalveolar lavage fluid for diagnosis of invasive aspergillosis: a bivariate metaanalysis and systematic review. PLoS One 2011; 6: e28467. 11. Avni T, Leibovici L, Paul M. PCR diagnosis of invasive candidiasis: systematic review and meta-analysis. J Clin Microbiol 2011; 49: 665–670. 12. Robenshtok E, Gafter-Gvili A, Goldberg E et al. Antifungal prophylaxis in cancer patients after chemotherapy or hematopoietic stem-cell transplantation: systematic review and meta-analysis. J Clin Oncol 2007; 25: 5471–5489. 13. Pechlivanoglou P, Le HH, Daenen S, Snowden JA, Postma MJ. Mixed treatment comparison of prophylaxis against invasive fungal infections in neutropenic patients receiving therapy for haematological malignancies: a systematic review. J Antimicrob Chemother 2014; 69: 1–11. 14. http://www.mercknewsroom.com/news-release/prescription-medicinenews/fda-approves-mercks-noxafil-posaconazole-injection-18-mgml-i (Accessed April 2014). 15. Mann PA, McNicholas PM, Chau AS et al. Impact of antifungal prophylaxis on colonization and azole susceptibility of Candida species. Antimicrob Agents Chemother 2009; 53: 5026–5034. 16. Imhof A, Balajee SA, Fredricks DN, Englund JA, Marr KA. Breakthrough fungal infections in stem cell transplant recipients receiving voriconazole. Clin Infect Dis 2004; 39: 743–746. 17. Pang KA, Godet C, Fekkar A et al. Breakthrough invasive mould infections in patients treated with caspofungin. J Infect 2012; 64: 424–429. 18. Pizzo PA, Robichaud KJ, Gill FA, Witebsky FG. Empiric antibiotic and antifungal therapy for cancer patients with prolonged fever and granulocytopenia. Am J Med 1982; 72: 101–111. 19. Cordonnier C, Robin C, Alanio A, Bretagne S. Antifungal pre-emptive strategy for high-risk neutropenic patients: why the story is still ongoing. Clin Microbiol Infect 2014; 20 (suppl): 27–35.
ª2014 The Authors Clinical Microbiology and Infection ª2014 European Society of Clinical Microbiology and Infectious Diseases, CMI, 20 (Suppl. 6), 1–4
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Clinical Microbiology and Infection, Volume 20 Supplement 6, June 2014
20. Cordonnier C, Pautas C, Maury S et al. Empirical versus preemptive antifungal therapy for high-risk, febrile, neutropenic patients: a randomized, controlled trial. Clin Infect Dis 2009; 48: 1042–1051. 21. Morrissey CO, Chen SC, Sorrell TC et al. Galactomannan and PCR versus culture and histology for directing use of antifungal treatment for invasive aspergillosis in high-risk haematology patients: a randomised controlled trial. Lancet Infect Dis 2013; 13: 519–528. 22. Hebart H, Klingspor L, Klingebiel T et al. A prospective randomized controlled trial comparing PCR-based and empirical treatment with liposomal amphotericin B in patients after allo-SCT. Bone Marrow Transplant 2009; 43: 553–561. 23. Donnelly JP, Maertens J. The end of the road for empirical antifungal treatment? Lancet Infect Dis 2013; 13: 470–472.
CMI
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ª2014 The Authors Clinical Microbiology and Infection ª2014 European Society of Clinical Microbiology and Infectious Diseases, CMI, 20 (Suppl. 6), 1–4