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Received Date : 18-Nov-2013 Revised Date : 06-Mar-2014 Accepted Date : 08-Mar-2014 Article type : Supplement Article “Antifungal stewardship in invasive Candida infections” 2nd revision

Invited article for a supplement edition in Clinical Microbiology and Infection Markus Ruhnke 1 1

Dept. of Internal Medicine, Charité University Medicine, Campus Charité Mitte, Berlin

Correspondence: Prof. Dr. med. Markus Ruhnke Medizinische Klinik und Poliklinik, m. S. Onkologie & Hämatologie Charité Universitätsmedizin Berlin, Campus Charité Mitte Charitéplatz 1, 10117 Berlin Phone:+49-(0)30-450-513102, fax: +49- (0)30-450-513907, Email: [email protected]

Keywords: invasive fungal infection, Candida, candidosis, antifungal stewardship, resistance, antifungal therapy

Abstract Bloodstream and other invasive infections due to Candida species (invasive fungal diseases = IFD) are a major cause of morbidity and mortality in hospitalized adults and children in many countries worldwide. The high infection-related morbidity and mortality associated with invasive Candida infection / candidaemia (IC/C), combined with suboptimal diagnostic tools, have driven the overuse of antifungal drugs. Antifungal stewardship (AFS) may be regarded as sub-entity of the more general term Antiinfective or Antimicrobial Stewardship Program (AIS/AMS). The high costs and high contribution of antifungal agents to the management of This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/1469-0691.12622 This article is protected by copyright. All rights reserved.

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IFDs along with their recognized toxicities has been addressed as the principal justification for antifungal stewardship. AFS programs should be organized by an interdisciplinary team of clinicians, pharmacists, microbiologists and infection control experts with the lead of an infectious disease specialist preferably in each large hospital /institution dealing with highrisk patients for invasive fungal infections. These programs should consider various aspects of IC/C including: 1) the local fungal epidemiology, 2) information on antifungal resistance rates, 3) establishing and application of therapeutic guidelines, 4) implementation of treatment strategies for empirical, pre-emptive therapy including PK/PD data for antifungal drugs, de-escalation and “switch and step-down strategies” (from intravenous to oral medication) in defined patient populations, 5) catheter management together with the application of routine diagnostic procedures such as ophthalmological and cardiac evaluations, and 6) the best available diagnostic tests for diagnosing IC and candidaemia. Introduction Infection-related mortality due to IC/C is remains high, in particular in severely ill patients in the ICU and when antifungal therapy is delayed (2;3). The high infection-related morbidity and mortality associated with IC, combined with suboptimal diagnostic tools, have driven the overuse of antifungal drugs in therapy and prophylaxis of IC/C. The concept of anti-infective stewardship may be defined as an ongoing effort by a healthcare institution to optimize antimicrobial use in order to improve patient outcomes, ensure cost-effective therapy, and reduce adverse sequelae (4). This includes the appropriate use of antimicrobials by selecting the proper drug, dosage, duration, and route of administration. Antimicrobial resistance—a consequence of the use and misuse of antimicrobial medicines—occurs when a microorganism becomes resistant to an antimicrobial drug to which it was previously sensitive. Primary and acquired (or secondary) resistance to antifungal drugs is known for several pathogenic fungi (e.g. yeasts such as Candida spp., and moulds such as Aspergillus spp or Mucorales) (5;6). Resistance mechanisms have been extensively described, in particular for Candida albicans against fluconazole with potential cross-resistance to other azole antifungals (6). Current issues related to treatment of invasive Candida infections include aspects such as choice of the optimal antifungal drug for candidaemia, balance between overuse (empirical therapy) and underuse (waiting until proven disease) of antifungal therapy in severely ill patients, step-down strategies, implementation of PK/PD in

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everyday practice, emergence of non- Candida-albicans infections, the role of non-cultural diagnostic tests, and pharmaco-economics (see table 1). Antifungal Stewardship for IC/C

According to the Policy Statement on Antimicrobial Stewardship by the Society for Healthcare Epidemiology of America (SHEA), the Infectious Diseases Society of America (IDSA), and the Pediatric Infectious Diseases Society (PIDS), antimicrobial stewardship (AMS) is defined as a program with coordinated interventions designed to improve and measure the appropriate use of antimicrobial agents by promoting the selection of the optimal antimicrobial drug regimen including dosing, duration of therapy, and route of administration (7) (see table 2). Antifungal stewardship (AFS) refers to a program or series of interventions to monitor and direct antifungal use at a health care institution. According to Tamma & Cosgrove, the most effective antimicrobial stewardship programs simultaneously incorporate multiple strategies after collaborating with the various specialties within a given health care facility, although interventions on a smaller scale to improve antimicrobial use are also valuable in some settings (8). An understanding of the pharmacokinetics and pharmacodynamics (PK/PD) of these drugs has been demonstrated as important to optimize drug choice and dosing regimen(9). Optimizing the use of currently available antifungal agents is not only influenced by antifungal drug properties (spectrum of activity, PK/PD, mode of action, route of application) but by their high cost and drug-related toxicities as well. However, reduction in healthcare costs should be regarded only as a secondary goal of AFS.

Challenges for the implementation of AFS in Candida infections Implementation of an AFS program using a comprehensive care bundle for the treatment of candidaemia has been shown to improve management of infected patients (10). Key issues of the strategy in a study from Michigan/USA were: 1) utilization appropriate antifungal drugs with appropriate duration of use, 2) removal of intravenous catheters, 3) adequate diagnostics with repeated blood cultures, and 4) performance of ophthalmologic examinations (10). In a prospective study on AFS in IC/C from Thailand, interventions included education, introduction of an antifungal hepatic and / or renal dose adjustment tool, antifungal prescription forms, and prescription-control strategies (11). For the implementation of an effective AFS program various important aspects and questions need to be considered.

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a)What are adequate diagnosis of IC/C and the role of non-cultural tests (e.g. Ag/Ab, ß-DGlucan, PCR)?

Blood cultures (BC) are still the method of choice for the diagnosis of candidaemia. Two pairs of blood culture bottles (10 ml each) should be obtained for aerobic and anaerobic culture when candidaemia is suspected before the initiation of antifungal therapy (12). Standard BC media detect most Candida species. It appears that the detection of C. glabrata is enhanced in anaerobic media. The addition of special fungal media may further enhance the speed and recovery of yeasts from blood („Mycosis-IC/F-Medium“ or BacT/ALERT 3D). Routine blood cultures are recommended after the initiation of antifungal therapy, either by day 3-5 and at the end of therapy or according to the current ESCMID Candida guideline even daily until negativity (13;14). In addition, Candida guidelines recommend, fundoscopy (and transoesophageal echocardiography) to detect organ involvement (13-15).

It is known for years that standard mycological diagnostics using conventional blood culture systems may fail to diagnose IC/C in up to 75% (16). Non-cultural tests (e.g. ß-D-Glucan, Candida antigen and antibody tests, molecular tests) have been advocated to close this diagnostic gap. Sensitivity (30-77%) and specificity (70-88%) of Candida antibody (AB) tests varies widely between different studies. Further improvements in the sensitivity (76%) was achieved by the combination of the Candida specific antigens (e.g. Platelia-Candida, BioRad) with the detection of specific antibodies (e.g. Platelia-Candida) (17;18). The detection of circulating 1,3-beta-D-Glucan (BDG) from the cell wall of yeasts has been suggested for the diagnosis of invasive candidosis. The test cannot distinguish between infections due to different fungal agents such as Candida, Aspergillus and Pneumocystis jirovecii (19-21).In a recent study from Italy in 377 patients, consecutively admitted to ICU for sepsis, 95 patients having an ICU stay of more than five days were studied (22). The positive and negative predictive values for a single-point BDG assay were higher than those of Candida score and Candida colonization index. Long-term ICU patients were found to have elevated BDG levels, not only due to invasive fungal infections, but also due to the serious underlying diseases and conditions (21). When BDG was compared to Candida-PCR, PCR was found to be more sensitive than BDG for diagnosing IC (23). In contrast to this “conventional” approach, one study using real-time PCR (with detection of six common Candida spp.) from serum samples was found to correlate positively with blood culture

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results but could give results within 1 day (24). Candida PCR is now regarded as the most promising tool for rapid diagnosis of IC/C and closing the “diagnostic gap” (16;23).

b)What is the role of Candida scoring systems or colonization index to detect IC/C? Some strategies suggested the use of prediction rules or specific scores (e.g. Candida scores, Candida colonisation index) to calculate the likelihood for acquiring invasive Candida disease (25-27). It has been shown that colonization must be multifocal with detection from multiple sampling to be significant. However, culturing Candida spp. from a non-sterile site does not reflect disease but mostly colonization and should not prompt initiation of systemic antifungal therapy. In fact, detection of Candida spp. in a single non-sterile sample (e.g. broncho-alveolar lavage) do not necessarily correlate with invasive disease and requires no systemic treatment (28). Even more difficult, Candida scores may not be able to distinguish between different Candida species. Whether these scores and/or prediction rules are widely accepted and applied in clinical practice is not known, but these models could help, together with better diagnostic methods, to apply antifungal drugs in a more directed way.

c)Which is the optimal antifungal drug treatment for candidaemia, importance of nonCandida albicans species and duration of therapy?

In every patient with documented IC/C, antifungal therapy should be started on all patients within 24 h after a blood (or tissue from sterile site) culture is positive for yeast (14;15). The preferred antifungal therapy for candidaemia and other systemic Candida infections is either an echinocandin, such as anidulafungin (200mg „loading dose“, then 100mg/day i.v.), caspofungin (70mg „loading dose“, then 50mg/day iv.) or micafungin (100mg/day iv. without „loading dose“) and as alternative in not critically ill patients without previous exposure to azoles or infection by fluconazole-resistant fungi fluconazole (400-800mg/day iv.; with double dose as „loading dose“ on day 1) (29-33) (see table 3). Fluconazole is generally effective for C/IC, but is not regarded as the first choice in critically ill patients. Its use may be further hampered by an increasing prevalence of infections due to Candida spp. with acquired or intrinsic resistance to fluconazole, such as C. glabrata and C. krusei. Recent guidelines favor the echinocandin class of antifungals as first-line therapy in haemodynamically unstable patients, in those with previous azole exposure, and in clinical settings with high local prevalence of fluconazole-resistant strains (14;15). Empiric therapy with fluconazole should not be used in critically ill patients with sepsis or septic shock. This article is protected by copyright. All rights reserved.

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Instead, an echinocandin or liposomal Amphotericin B should be used in these patients. The use of D-AMB is associated with significant toxicity (infusion-related electrolyte imbalances and nephrotoxicity). Its use is therefore discouraged outside resource poor settings as a first line agent for the treatment of IC. Candida albicans is still regarded as the most prevalent Candida spp. (>60-70%) in BSI but the proportion on non-Candida-albicans spp. exceeds 50-60% in some surveys(34). In various reports from Europe (e.g. Denmark, Spain), the proportion of Candida isolates non-susceptible to fluconazole was increasing over the recent years (34;35). Prior fluconazole treatment has been described as an independent risk factor for candidaemia caused by microbiologically confirmed fluconazole resistant species in many but not all studies (36;37). In a seminational surveillance study from Denmark, the proportion of Candida bloodstream isolates isolates with decreased susceptibility to fluconazole exceeded 30% in 2006 (35). However, this trend was not observed in all European countries (e.g. Switzerland) (38). Infection control and mycological surveillance of Candida resistance and emergence of non-Candida-albicans spp. need to be monitored closely. In centres with high prevalence of IC, infection control programs are needed (e.g. strict hand hygiene) to reduce nosocomial infection rates. Most importantly, antifungal treatment for uncomplicated candidaemia is recommended for 14 days after the first negative blood culture and together with resolution of all clinical signs of infection.

d)How to balance between overuse (empirical therapy) and underuse (waiting until proven disease) of antifungal therapy in severely ill patients

The high infection-related morbidity and mortality associated with invasive Candida infection (IC), combined with suboptimal diagnostic tools, have driven the overuse of antifungal drugs in particular for empiric therapy of presumed IC. Antifungal agents (e.g. fluconazole) are widely used for prophylaxis and empirical therapy of suspected invasive Candida infection in ICU patients. Certain patients groups in the ICU may benefit from prophylactic use but currently, the optimal target population for antifungal prophylaxis remains unknown, as this question has not been sufficiently addressed in clinical trials (13;39;40). Currently, only patients who had undergone abdominal surgery and who had recurrent gastrointestinal perforations or anastomotic leakages should be regarded as candidates for fluconazole prophylaxis but not the vast majority of SICU patients (40). According to a meta-analysis on fluconazole prophylaxis in surgical ICU patients (SICU), prophylactic fluconazole administration for prevention of mycoses in SICU patients appears This article is protected by copyright. All rights reserved.

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to successfully decrease the rate of these infections, but this strategy does not necessarily improve survival (41). Because of the potential for both resistance and emergence of nonCandida albicans isolates, clinicians must consider these issues when evaluating fluconazole prophylaxis in the SICU.

In the ICU, empirical antifungal therapy against suspected Candida infections (e.g. with positive biomarkers such as ß-D-Glucan) is commonly applied in clinical practice and supported by the IDSA Clinical Practice Guidelines for the Management of Candidiasis (15). The concept of AFS can be directly applied to the prescription of empirical antifungal (and antibiotic) therapy in the intensive care unit (ICU) because it is well-known that inappropriate initial regimens lead to increased mortality (42). In a study from a hospital in the US in 1999, inappropriate initial antimicrobial/antifungal therapy was observed in 86.6% of patients with candidemia (42). Physicians taking care of immunocompromised patients tend to overuse antifungals. Doctors are worried about a seriously ill patient with sepsis or shock and tend to start empirical antifungal therapy when antibiotic therapy failed. If antifungal therapy is not started within 24 hrs after the diagnosis of Candida septic shock overall fatality rate is close to 100% (43). In contrast, a study on empirical therapy with fluconazole in febrile ICU patients with FUO but without shock did not show a benefit over placebo for this treatment approach (44). Empirical antifungal therapy for suspected invasive Candida infection in the ICU may lead to overuse of antifungal drugs and should not be regarded as standard of care unless the use of additional diagnostic tools (e.g. biomarkers) indicate invasive disease (45).

e)When to apply step-down / de-escalation strategies? De-escalation strategies (switch from i.v. echinocandin therapy after initial response to oral therapy with an azole antifungal drug) are commonly used. However, criteria for “early switch” (e.g. after 3 to 5 days) are not clearly established in contrast to “late switch” after 10 days of effective therapy as recommended in current guidelines (13;14). After improvement of clinical signs, sterilisation of blood cultures and documented in vitro susceptibility of the causative yeast, step down therapy after initial treatment with an echinocandin (anidulafungin, caspofungin and micafungin) was shown to be effective with oral fluconazole (or voriconazole) starting on day 10 of antifungal therapy, and may be recommended if oral drug intake and gastrointestinal absorption is possible. (31;32;46;47) Importantly, further criteria may apply, such as identification of a susceptible organism in a clinically stable patient with negative blood culture results. This article is protected by copyright. All rights reserved.

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f)How important is the catheter removal in IC/C? Central venous lines should be regarded as an infectious focus of candidaemia and should be removed whenever possible, regardless if they are the primary portal of entry or if they are secondarily colonised (15;48). A rapid sterilisation of the bloodstream is only achieved by the removal of infected central venous lines including implanted catheters (e.g. Port-/Hickman/Broviac-Systems). Removal should be done together with the initiation of antifungal therapy. If the central venous lines are retained, the duration of candidaemia increases (from 3 to 6 days) as does the mortality of patients (48-51) . This is particularly supported by data for infections due to C. albicans and C. parapsilosis, but less for other Candida species. The best time for removal is controversial but should generally be done as early as possible.

g)How to achieve the most cost-effective antifungal therapy (pharmacoeconomics)? In general, treatment of patients with invasive fungal infections may be associated with significantly higher inpatient hospital cost compared with controls (52). In a large a propensity analysis in an estimated 1118 hospital admissions of paediatric patients and 8949 hospital admissions of adult patients from the US in 2000, in adult patients, candidaemia was associated with a increase in mortality, increase in length of stay, and a mean increase in hospital charges(53). According to a case-control study from the US, candidaemia itself did not increase the total hospital charges and cost of hospitalization; having received adequate treatment for candidaemia, but significantly increased the total hospital charges and cost of hospitalization (54;55). Toxicity of the “old” antifungals (e.g. amphotericin B deoxycholate) was of major concern in the past but there were not many choices. Newer antifungal agents (e.g. liposomal amphotericin B, echinocandins) are not only safer, but have equal or even better efficacy and are easier to administer (9). Unfortunately, most of these newer antifungal drugs are more expensive and physicians are confronted to regulations by hospital administrators and pharmacists to reduce or even avoid their use in clinical practice during hospital stay for financial reasons (at least in Europe common practice). Certainly, this may differ from institution to institution. Not only due to cost issues but to decrease high rate of multidrug-resistant pathogens (MDRP) in the hospital, formulary restrictions and preauthorization strategies are discussed in the literature on AMS/AFS (11;56).

Several recent pharmaco-economic studies have indicated that “newer” antifungal agents (e.g. echinocandins) are associated with higher directly drug-related pharmacy costs. Most studies This article is protected by copyright. All rights reserved.

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examined different parameters and are therefore difficult to compare. In a recent analysis, micafungin (MICA) was regarded as a more cost-effective therapy in the treatment of IC/C when compared with L-AMB, primarily because of less nephrotoxicity using MICA and less direct drug costs (57). A direct economic comparison between echinocandins, found MICA to be cost-equivalent to caspofungin in treating IC/C, with variation in drug acquisition cost the critical factor (58).

In an economic analysis of fluconazole versus anidulafungin (AND), Neoh et al. found AND to be cost-effective despite higher directly drug-related cost with AND (59). This model calculated the lower overall mortality rates in favour of AND in patients treated with for IC/C which lead to this conclusion.

It may be concluded, that no substantial increase of the total cost for the patient care treated for IC/C are observed with “newer” antifungal agents because other “indirect” costs may be reduced (e.g. treatment of adverse events, reduced length of hospital stay, mortality) and economic differences in use of antifungal drugs may be influenced by several factors (52;57;59;60). The higher drug-related costs have to be balanced with the clinical benefit and patient outcome.

Implementation of an AFS for IC/C in the hospital Implementation of an AFS program for IC/C requires a multidisciplinary approach and it was suggested that an infectious diseases physician and a clinical pharmacist with infectious diseases training are its core team members (61). In addition, a clinical microbiologist and infection control expert need to be involved in order to address the emergence of MDRP and infection control issues adequately (62) (see table 2).

The implementation of national or international guidelines written from experts in the field is a first step to adapt recommendations from guidelines into local everyday practice (13-15;63). Recently, in the UK the compliance and implementation of the British Society for Medical Mycology standards of care for patients with invasive infections in UK hospitals was audited. Apparently, recommendations which are believed to be essential for adequate patient care, such as early removal of the central venous catheter (CVC) were followed in the majority of patients (64). In patients presenting with candidaemia, CVCs were changed routinely within 48h in 85%. It has been shown, that compliance with a specific AFS program depends on ID This article is protected by copyright. All rights reserved.

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specialist consultation (e.g. routine ophthalmological examinations to exclude systemic IC) (65). Thus, guidance appears to be helpful but there is substantial room for improvement, in particular how to use and apply diagnostic tests, antifungal agents and restriction policies.

In summary, AFS programs should be organized by an interdisciplinary team of clinicians, pharmacists, microbiologists and infection control experts with the lead of an infectious disease specialist preferably in each large hospital /institution dealing with high-risk patients for invasive fungal infections. These programs should consider various aspects of IC/C including: 1) the local fungal epidemiology, 2) information on antifungal resistance rates, 3) establishing and application of therapeutic guidelines, 4) implementation of treatment strategies for empirical, pre-emptive therapy including PK/PD data for antifungal drugs, deescalation and “switch and step-down strategies” (from intravenous to oral medication) in defined patient populations, 5) catheter management together with the application of routine diagnostic procedures such as ophthalmological and cardiac evaluations, and 6) the best available diagnostic tests for diagnosing IC and candidaemia. Reference List (1) Ananda-Rajah MR, Slavin MA, Thursky KT. The case for antifungal stewardship. Curr Opin Infect Dis 2012 Feb;25(1):107-15. (2) Nolla-Salas J, Sitges-Serra A, Leon-Gil C, Martinez-Gonzalez J, Leon-Regidor MA, Ibanez-Lucia P, et al. Candidemia in non-neutropenic critically ill patients: analysis of prognostic factors and assessment of systemic antifungal therapy. Study Group of Fungal Infection in the ICU. Intensive Care Med 1997 Jan;23(1):23-30. (3) Morrell M, Fraser VJ, Kollef MH. Delaying the empiric treatment of candida bloodstream infection until positive blood culture results are obtained: a potential risk factor for hospital mortality. Antimicrob Agents Chemother 2005 Sep;49(9):3640-5. (4) MacDougall C, Polk RE. Antimicrobial stewardship programs in health care systems. Clin Microbiol Rev 2005 Oct;18(4):638-56. (5) Chamilos G, Kontoyiannis DP. Update on antifungal drug resistance mechanisms of Aspergillus fumigatus. Drug Resist Updat 2005 Dec;8(6):344-58. (6) Sanglard D, Odds FC. Resistance of Candida species to antifungal agents: molecular mechanisms and clinical consequences. Lancet Infect Dis 2002 Feb;2(2):73-85. (7) Society for Healthcare Epidemiology of America (SHEA), Infectious Diseases Society of America (IDSA), Pediatric Infectious Diseases Society (PIDS). Policy statement on antimicrobial stewardship by the Society for Healthcare Epidemiology of America (SHEA), the Infectious Diseases Society of America (IDSA), and the

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Pediatric Infectious Diseases Society (PIDS). Infect Control Hosp Epidemiol 2012 Apr;33(4):322-7. (8) Tamma PD, Cosgrove SE. Antimicrobial stewardship. Infect Dis Clin North Am 2011 Mar;25(1):245-60. (9) Andes D, Pascual A, Marchetti O. Antifungal therapeutic drug monitoring: established and emerging indications. Antimicrob Agents Chemother 2009 Jan;53(1):24-34. (10) Antworth A, Collins CD, Kunapuli A, Klein K, Carver P, Gandhi T, et al. Impact of an antimicrobial stewardship program comprehensive care bundle on management of candidemia. Pharmacotherapy 2013 Feb;33(2):137-43. (11) Apisarnthanarak A, Yatrasert A, Mundy LM. Impact of education and an antifungal stewardship program for candidiasis at a Thai tertiary care center. Infect Control Hosp Epidemiol 2010 Jul;31(7):722-7. (12) Ruhnke M, Böhme A, Buchheidt D, Donhuijsen K, Einsele H, Enzensberger R, et al. Diagnosis of invasive fungal infections in hematology and oncology--guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO). Ann Hematol 2003 Oct;82 Suppl 2:S141-S148. (13) Cornely OA, Bassetti M, Calandra T, Garbino J, Kullberg BJ, Lortholary O, et al. ESCMID* guideline for the diagnosis and management of Candida diseases 2012: non-neutropenic adult patients. Clin Microbiol Infect 2012 Dec;18 Suppl 7:19-37. (14) Ruhnke M, Rickerts V, Cornely OA, Buchheidt D, Glockner A, Heinz W, et al. Diagnosis and therapy of Candida infections: joint recommendations of the German Speaking Mycological Society and the Paul-Ehrlich-Society for Chemotherapy. Mycoses 2011 Jul;54(4):279-310. (15) Pappas PG, Kauffman CA, Andes D, Benjamin DK, Jr., Calandra TF, Edwards JE, Jr., et al. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis 2009 Mar 1;48(5):503-35. (16) 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 May;56(9):1284-92. (17) Sendid B, Poirot JL, Tabouret M, Bonnin A, Caillot D, Camus D, et al. Combined detection of mannanaemia and antimannan antibodies as a strategy for the diagnosis of systemic infection caused by pathogenic Candida species. J Med Microbiol 2002 May;51(5):433-42. (18) Sendid B, Caillot D, Baccouch-Humbert B, Klingspor L, Grandjean M, Bonnin A, et al. Contribution of the Platelia Candida-specific antibody and antigen tests to early diagnosis of systemic Candida tropicalis infection in neutropenic adults. J Clin Microbiol 2003 Oct;41(10):4551-8. (19) Odabasi Z, Mattiuzzi G, Estey E, Kantarjian H, Saeki F, Ridge RJ, et al. Beta-Dglucan as a diagnostic adjunct for invasive fungal infections: validation, cutoff This article is protected by copyright. All rights reserved.

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development, and performance in patients with acute myelogenous leukemia and myelodysplastic syndrome. Clin Infect Dis 2004 Jul 15;39(2):199-205. (20) Ostrosky-Zeichner L, Alexander BD, Kett DH, Vazquez J, Pappas PG, Saeki F, et al. Multicenter clinical evaluation of the (1-->3) beta-D-glucan assay as an aid to diagnosis of fungal infections in humans. Clin Infect Dis 2005 Sep 1;41(5):654-9. (21) Presterl E, Parschalk B, Bauer E, Lassnigg A, Hajdu S, Graninger W. Invasive fungal infections and (1,3)-beta-D-glucan serum concentrations in long-term intensive care patients. Int J Infect Dis 2009 Nov;13(6):707-12. (22) Posteraro B, De PG, Tumbarello M, Torelli R, Pennisi MA, Bello G, et al. Early diagnosis of candidemia in intensive care unit patients with sepsis: a prospective comparison of (1-->3)-beta-D-glucan assay, Candida score, and colonization index. Crit Care 2011;15(5):R249. (23) Nguyen MH, Wissel MC, Shields RK, Salomoni MA, Hao B, Press EG, et al. Performance of Candida Real-time Polymerase Chain Reaction, beta-D-Glucan Assay, and Blood Cultures in the Diagnosis of Invasive Candidiasis. Clin Infect Dis 2012 May;54(9):1240-8. (24) McMullan R, Metwally L, Coyle PV, Hedderwick S, McCloskey B, O'Neill HJ, et al. A prospective clinical trial of a real-time polymerase chain reaction assay for the diagnosis of candidemia in nonneutropenic, critically ill adults. Clin Infect Dis 2008 Mar 15;46(6):890-6. (25) Ostrosky-Zeichner L, Sable C, Sobel J, Alexander BD, Donowitz G, Kan V, et al. Multicenter retrospective development and validation of a clinical prediction rule for nosocomial invasive candidiasis in the intensive care setting. Eur J Clin Microbiol Infect Dis 2007 Apr;26(4):271-6. (26) Leon C, Ruiz-Santana S, Saavedra P, Galvan B, Blanco A, Castro C, et al. Usefulness of the "Candida score" for discriminating between Candida colonization and invasive candidiasis in non-neutropenic critically ill patients: a prospective multicenter study. Crit Care Med 2009 May;37(5):1624-33. (27) Eggimann P, Garbino J, Pittet D. Management of Candida species infections in critically ill patients. Lancet Infect Dis 2003 Dec;3(12):772-85. (28) Meersseman W, Lagrou K, Spriet I, Maertens J, Verbeken E, Peetermans WE, et al. Significance of the isolation of Candida species from airway samples in critically ill patients: a prospective, autopsy study. Intensive Care Med 2009 Sep;35(9):1526-31. (29) Rex JH, Bennett JE, Sugar AM, Pappas PG, van der Horst CM, Edwards JE, et al. A randomized trial comparing fluconazole with amphotericin B for the treatment of candidemia in patients without neutropenia. Candidemia Study Group and the National Institute. N Engl J Med 1994 Nov 17;331(20):1325-30. (30) Rex JH, Pappas PG, Karchmer AW, Sobel J, Edwards JE, Hadley S, et al. A randomized and blinded multicenter trial of high-dose fluconazole plus placebo versus fluconazole plus amphotericin B as therapy for candidemia and its consequences in nonneutropenic subjects. Clin Infect Dis 2003 May 15;36(10):1221-8. This article is protected by copyright. All rights reserved.

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(31) Mora-Duarte J, Betts R, Rotstein C, Colombo AL, Thompson-Moya L, Smietana J, et al. Comparison of caspofungin and amphotericin B for invasive candidiasis. N Engl J Med 2002 Dec 19;347(25):2020-9. (32) Reboli AC, Rotstein C, Pappas PG, Chapman SW, Kett DH, Kumar D, et al. Anidulafungin versus fluconazole for invasive candidiasis. N Engl J Med 2007 Jun 14;356(24):2472-82. (33) Kuse ER, Chetchotisakd P, da Cunha CA, Ruhnke M, Barrios C, Raghunadharao D, et al. Micafungin versus liposomal amphotericin B for candidaemia and invasive candidosis: a phase III randomised double-blind trial. Lancet 2007 May 5;369(9572):1519-27. (34) Puig-Asensio M, Padilla B, Garnacho-Montero J, Zaragoza O, Aguado JM, Zaragoza R, et al. Epidemiology and predictive factors for early and late mortality in Candida bloodstream infections: a population-based surveillance in Spain. Clin Microbiol Infect 2013 Aug 29. (35) Arendrup MC, Fuursted K, Gahrn-Hansen B, Schonheyder HC, Knudsen JD, Jensen IM, et al. Semi-national surveillance of fungaemia in Denmark 2004-2006: increasing incidence of fungaemia and numbers of isolates with reduced azole susceptibility. Clin Microbiol Infect 2008 May;14(5):487-94. (36) Garnacho-Montero J, az-Martin A, Garcia-Cabrera E, Ruiz Perez de PM, HernandezCaballero C, znar-Martin J, et al. Risk factors for fluconazole-resistant candidemia. Antimicrob Agents Chemother 2010 Aug;54(8):3149-54. (37) Shorr AF, Lazarus DR, Sherner JH, Jackson WL, Morrel M, Fraser VJ, et al. Do clinical features allow for accurate prediction of fungal pathogenesis in bloodstream infections? Potential implications of the increasing prevalence of non-albicans candidemia. Crit Care Med 2007 Apr;35(4):1077-83. (38) Marchetti O, Bille J, Fluckiger U, Eggimann P, Ruef C, Garbino J, et al. Epidemiology of candidemia in Swiss tertiary care hospitals: secular trends, 19912000. Clin Infect Dis 2004 Feb 1;38(3):311-20. (39) Pelz RK, Hendrix CW, Swoboda SM, ener-West M, Merz WG, Hammond J, et al. Double-blind placebo-controlled trial of fluconazole to prevent candidal infections in critically ill surgical patients. Ann Surg 2001 Apr;233(4):542-8. (40) Eggimann P, Francioli P, Bille J, Schneider R, Wu MM, Chapuis G, et al. Fluconazole prophylaxis prevents intra-abdominal candidiasis in high-risk surgical patients. Crit Care Med 1999 Jun;27(6):1066-72. (41) Shorr AF, Chung K, Jackson WL, Waterman PE, Kollef MH. Fluconazole prophylaxis in critically ill surgical patients: a meta-analysis. Crit Care Med 2005 Sep;33(9):1928-35. (42) Arnold HM, Micek ST, Skrupky LP, Kollef MH. Antibiotic stewardship in the intensive care unit. Semin Respir Crit Care Med 2011 Apr;32(2):215-27.

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(43) Kollef M, Micek S, Hampton N, Doherty JA, Kumar A. Septic shock attributed to Candida infection: importance of empiric therapy and source control. Clin Infect Dis 2012 Jun;54(12):1739-46. (44) Schuster MG, Edwards JE, Jr., Sobel JD, Darouiche RO, Karchmer AW, Hadley S, et al. Empirical fluconazole versus placebo for intensive care unit patients: a randomized trial. Ann Intern Med 2008 Jul 15;149(2):83-90. (45) Hanson KE, Pfeiffer CD, Lease ED, Balch AH, Zaas AK, Perfect JR, et al. beta-Dglucan surveillance with preemptive anidulafungin for invasive candidiasis in intensive care unit patients: a randomized pilot study. PLoS ONE 2012;7(8):e42282. (46) Kullberg BJ, Sobel JD, Ruhnke M, Pappas PG, Viscoli C, Rex JH, et al. Voriconazole versus a regimen of amphotericin B followed by fluconazole for candidaemia in nonneutropenic patients: a randomised non-inferiority trial. Lancet 2005 Oct 22;366(9495):1435-42. (47) Pappas PG, Rotstein CM, Betts RF, Nucci M, Talwar D, De Waele JJ, et al. Micafungin versus caspofungin for treatment of candidemia and other forms of invasive candidiasis. Clin Infect Dis 2007 Oct 1;45(7):883-93. (48) Rex JH, Bennett JE, Sugar AM, Pappas PG, Serody J, Edwards JE, et al. Intravascular catheter exchange and duration of candidemia. NIAID Mycoses Study Group and the Candidemia Study Group. Clin Infect Dis 1995 Oct;21(4):994-6. (49) Blumberg HM, Jarvis WR, Soucie JM, Edwards JE, Patterson JE, Pfaller MA, et al. Risk factors for candidal bloodstream infections in surgical intensive care unit patients: the NEMIS prospective multicenter study. The National Epidemiology of Mycosis Survey. Clin Infect Dis 2001 Jul 15;33(2):177-86. (50) Wenzel RP, Gennings C. Bloodstream infections due to Candida species in the intensive care unit: identifying especially high-risk patients to determine prevention strategies. Clin Infect Dis 2005 Sep 15;41 Suppl 6:S389-S393. (51) Labelle AJ, Micek ST, Roubinian N, Kollef MH. Treatment-related risk factors for hospital mortality in Candida bloodstream infections. Crit Care Med 2008 Nov;36(11):2967-72. (52) Dodds AE, Drew R, Johnson M, Danna R, Dabrowski D, Walker V, et al. Cost of invasive fungal infections in the era of new diagnostics and expanded treatment options. Pharmacotherapy 2012 Oct;32(10):890-901. (53) Zaoutis TE, Argon J, Chu J, Berlin JA, Walsh TJ, Feudtner C. The epidemiology and attributable outcomes of candidemia in adults and children hospitalized in the United States: a propensity analysis. Clin Infect Dis 2005 Nov 1;41(9):1232-9. (54) Morgan J, Meltzer MI, Plikaytis BD, Sofair AN, Huie-White S, Wilcox S, et al. Excess mortality, hospital stay, and cost due to candidemia: a case-control study using data from population-based candidemia surveillance. Infect Control Hosp Epidemiol 2005 Jun;26(6):540-7.

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(55) Hassan I, Powell G, Sidhu M, Hart WM, Denning DW. Excess mortality, length of stay and cost attributable to candidaemia. J Infect 2009 Nov;59(5):360-5. (56) Drew RH, White R, MacDougall C, Hermsen ED, Owens RC, Jr. Insights from the Society of Infectious Diseases Pharmacists on antimicrobial stewardship guidelines from the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America. Pharmacotherapy 2009 May;29(5):593-607. (57) Cornely OA, Sidhu M, Odeyemi I, van Engen AK, van der Waal JM, Schoeman O. Economic analysis of micafungin versus liposomal amphotericin B for treatment of candidaemia and invasive candidiasis in Germany. Curr Med Res Opin 2008 Jun;24(6):1743-53. (58) Neoh CF, Liew D, Slavin MA, Marriott D, Chen SC, Morrissey O, et al. Economic Evaluation of Micafungin versus Caspofungin for the Treatment of Candidaemia and Invasive Candidiasis. Intern Med J 2013 Mar 6. (59) Neoh CF, Liew D, Slavin M, Marriott D, Chen SC, Morrissey O, et al. Costeffectiveness analysis of anidulafungin versus fluconazole for the treatment of invasive candidiasis. J Antimicrob Chemother 2011 Aug;66(8):1906-15. (60) Wingard JR, Wood CA, Sullivan E, Berger ML, Gerth WC, Mansley EC. Caspofungin versus amphotericin B for candidemia: a pharmacoeconomic analysis. Clin Ther 2005 Jun;27(6):960-9. (61) Drew RH. Antimicrobial stewardship programs: how to start and steer a successful program. J Manag Care Pharm 2009 Mar;15(2 Suppl):S18-S23. (62) Infectious Diseases Society of America (IDSA), Society for Healthcare Epidemiology of America (SHEA), Pediatric Infectious Diseases Society (PIDS). Policy statement on antimicrobial stewardship by the Society for Healthcare Epidemiology of America (SHEA), the Infectious Diseases Society of America (IDSA), and the Pediatric Infectious Diseases Society (PIDS). Infect Control Hosp Epidemiol 2012 Apr;33(4):322-7. (63) Denning DW, Kibbler CC, Barnes RA. British Society for Medical Mycology proposed standards of care for patients with invasive fungal infections. Lancet Infect Dis 2003 Apr;3(4):230-40. (64) Schelenz S, Barnes RA, Kibbler CC, Jones BL, Denning DW. Standards of care for patients with invasive fungal infections within the United Kingdom: a national audit. J Infect 2009 Feb;58(2):145-53. (65) Popovich K, Malani PN, Kauffman CA, Cinti SK. Compliance With Infectious Diseases Society of America Guidelines for Ophthalmologic Evaluation of Patients With Candidemia. Infectious Diseases in Clinical Practice 2010;15(4):254-6.

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Table 1: Current issues related to treatment of invasive Candida infections Which is the optimal antifungal drug treatment for candidaemia? How to balance between overuse (empirical therapy) and underuse (waiting until proven disease) of antifungal therapy in severely ill patients How long do handle central lines and do we need to treat in patients with catheter-related candidaemia vs. other forms of invasive Candida infections? What is the importance of Candida non-albicans infections for the choice of initial therapy? What is the appropriate choice of drugs in patient groups/hospitals with high prevalence of azole resistance? What is the role of non-cultural tests (e.g. Ag/Ab, ß-D-Glucan, PCR)? Should different patient populations be treated differently (e.g. granulocytopenic)? How to treat patients with invasive Candida infection and organ failure (e.g. renal and/or liver), severe sepsis or septic shock? When to apply step-down strategies (switch from i.v. to oral)? When and how to implement PK/PD in everyday antifungal treatment? Which antifungal therapy is most cost-effective (pharmacoeconomics)? Table 2: Minimum requirements for developing an institutional program to enhance Antifungal Stewardship (adapted from Policy Statement on Antimicrobial Stewardship by the Society for Healthcare Epidemiology of America (SHEA), the Infectious Diseases Society of America (IDSA), and the Pediatric Infectious Diseases Society (PIDS) Creation of a multidisciplinary interprofessional antifungal stewardship team that is physician directed or supervised. Team members should include but are not limited to: - a physician - a pharmacist - a clinical microbiologist - an infection preventionist. Institutional guidelines for the management of invasive Candida infections / candidaemia Additional interventions to improve the use of antifungals, including those designed to detect and eliminate: - Multidrug regimens with unnecessarily redundant antimicrobial spectra. - Antifungal therapy for the management of “fever” syndromes (without detection of fungi in sterile specimen) or cultures that represent contamination or routine colonization. - Empiric regimens that are inadequately - Regimens that do not adequately treat infections caused by culture-confirmed pathogens. Processes to measure and monitor antifungal use at the institutional level for internal benchmarking. Periodic distribution of facility-specific epidemiological data together with the rates of relevant in vitro susceptibilities to Candida pathogens. Table 3: Recommendations for non-granulocytopenic adults with IC/C in three different guidelines: 1) joint recommendations of the German Speaking Mycological Society (DMykG) / Paul-Ehrlich-Society for Chemotherapy (PEG), 2) Infectious Disease Society of

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Accepted Article

America (IDSA), and 3) European Society for Clinical Microbiology and Infectious Diseases (ESCMID) Antifungal drug Monotherapy

Polyenes Amphotericin B Deoxycholat (DAMB) Liposomal Amphotericin B (L-AMB) Amphotericin Lipid Complex (ABLC) Echinocandins Anidulafungin Caspofungin**

Micafungin*** Azoles Fluconazole

Voriconazole

Dosage* DMykG&

Evidence IDSA&

ESCMID

0,7-1,0 mg/kg/d

C-I

A-I

D-I

3 mg/kg/d 5 mg/kg/d

A-I C-II

A-I A-I

B-I C-II

day 1, loading 200mg/d from day 2, 100mg/d day 1, loading 70mg/d From day 2 1x50mg/d 1x100mg/d (without loading on day1)

A-I

A-I

A-I

A-I

A-I

A-I

A-I

A-I

A-I

Day 1 loading (double dose) From day 2 400-800mg/d Day 1, 2x6mg/kg/d loading From day 2, 2x3mg/kg/d

A-I

A-I

C-I

A-I

A-I

B-I

0,7mg/kg/d

B-I

B-III for endophthal mitis; A-III for endophthal mitis; Generally recommen ded for endocardit is, meningitis) B-III (CNS)

D-I

Combination therapy

Amphotericin B desoxycholate + fluconazole

800mg/d

Amphotericin B desoxycholate + flucytosine

0,7-1,0 mg/kg/d 4x25 mg/kg/d

Lipid Amphotericin B + flucytosine

C-III

No data

D-II

No data

* all dosages are indicated for intravenous application & Evidence according to IDSA criteria (please see Pappas PG et al, CID 2009) # ABCD is not listed here, because it is not licensed in many European countries ** Dose modification in patients with more than 80kg and with liver failure *** 1) Dose modifications in patients

Antifungal stewardship in invasive Candida infections.

Bloodstream and other invasive infections due to Candida species (invasive fungal diseases = IFD) are a major cause of morbidity and mortality in hosp...
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