Section 1: New Antifungal Therapeutics Subsection 1a: Posaconazole IV and Oral Delayed-Release Tablet

Russell E. Lewis, PharmD

Background Posaconazole is a broad-spectrum, triazole antifungal with clinically useful activity against a wide range of fungal pathogens including Candida spp., Aspergillus spp., and most Mucorales. Similar to other triazoles, posaconazole blocks the synthesis of ergosterol, a key component of the fungal cell membrane, through inhibition of cytochrome P-450-dependent enzyme lanosterol 14α-demethylase (Torres 2005). Posaconazole was initially developed as an oral suspension and subsequently approved by the US Food and Drug Administration (FDA) for the prevention of invasive fungal infections (IFI) in immunocompromised patients, including hematologic malignancy patients with prolonged neutropenia from chemotherapy (Cornely 2007) as well as hematopoietic stem-cell transplant (HSCT) patients with graft-versus-host disease (GVHD) (Ullmann 2007; FDA 2014). However, the suspension formulation needed to be administered multiple times a day (ie, 200 mg, 3 times daily) with food (preferably a high-fat meal) or a nutritional supplement to ensure adequate oral absorption. Some patients with chemotherapy-associated nausea or vomiting, mucositis or diarrhea, or GVHD could not adequately absorb posaconazole suspension to achieve effective blood levels (Table 1), which predisposed this subset of patients to increased risk of breakthrough fungal infection (Dolton 2012). Table 1. Steady-state geometric mean (% coefficient of variation) pharmacokinetic parameters in the clinical trials of posaconazole oral suspension. Data extracted from (US FDA 2014).

To address this limitation, a new delayed-release tablet (100 mg) and intravenous formulation (18 mg/L) of posaconazole were developed and recently approved by the FDA. Both formulations circumvent the absorption problems of the oral suspension and allow for posaconazole to be administered once daily after a twice-daily loading dose on the first day.

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Delayed-Release Tablets Posaconazole is a weak base with low aqueous solubility. Absorption of the suspension requires dissolution of the drug in the stomach prior to arrival in the duodenum and jejunum, where the drug is primarily absorbed through passive mechanisms (Figure 1). The rate and extent of posaconazole dissolution is maximized when the drug is taken as smaller, more frequent doses with a high-fat meal, which lowers gastric pH, prolongs gastric residence time, and stimulates splanchnic blood and bile flow. Patients with poor appetite, rapid gastric transit, or elevated gastric pH will have slower rates and extent of posaconazole dissolution, resulting in less absorbable drug delivered to the duodenum. Intraluminal pH is 4 to 5 in the duodenum but becomes progressively more alkaline, approaching 8 in the lower ileum. Therefore, further dissolution and absorption of posaconazole is diminished as the drug travels through the intestine (Dolton 2012).

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The new tablet formulation uses pH-sensitive polymers to release posaconazole at a controlled rate in the duodenum, thereby circumventing many of the problems associated with poor gastric dissolution of the drug (Percival 2014). As a result, following a loading dose (300 mg twice daily on day 1), the average serum concentration achieved with a 300-mg daily dose using delayed-release posaconazole tablets is 1400 ng/mL, which is more than double that achieved with the oral suspension administered at 200 mg 4 times daily (517 ng/mL) (Ezzet 2005; Duarte 2012). The tablet formulation also provides the opportunity to administer a loading dose on the first day of therapy to ensure therapeutic posaconazole plasma levels in the first 24 to 48 hours. This is in contrast with the oral suspension, which typically would not approach steady-state therapeutic levels until 7 to 10 days of therapy (Merck 2014).

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Another advantage of the delayed-release tablet formulation of posaconazole is that coadministration of medications that affect gastric pH (antacids, H2-receptor antagonists, proton pump inhibitors) does not significantly decrease the bioavailability of the delayed-release tablet as observed with the oral suspension (20% to 40% decrease in mean AUC). However, coadministration of the tablet with the prokinetic agent metoclopramide resulted in modest decreases in the Cmax (14%) and AUC (7%) of the delayed-release tablet (Kraft 2014). When administered orally to healthy volunteers, posaconazole delayed-release tablets are absorbed after a median of 4 to 5 hours, with a Cmax of 2764 ng/mL. The absolute bioavailability of the tablet is 54% but is still improved if given with a high-fat meal (15% increase in Cmax and 51% increase in AUC). Therefore, it is still recommended that the delayed-release tablets be administered with food whenever possible. In clinical trials, posaconazole tablets were well tolerated and had a similar safety profile to the posaconazole oral suspension (Merck 2014).. Intravenous Formulation One limitation of the tablet formulation is that it cannot be divided or crushed, which could limit its use in critically ill patients. Recently, an intravenous formulation of posaconazole (18 mg/L of posaconazole solubilized in sulfobutyl ether beta cyclodextrin) was approved by the FDA. In an open-label, 2-phase multicenter study in patients with acute myeloid leukemia (AML), myelodysplasia, or post-allogeneic HSCT, posaconazole 300 mg was administered intravenously twice on day 1 followed by 300 mg daily for 4 to 13 days. (Similar to the tablet formulation, an intravenous loading dose is recommended to achieve steady-state-like trough concentrations >1000 ng/mL during the first 24 hours of therapy.) Patients were allowed to switch to the oral suspension (400 mg twice daily or 300 mg 3 times daily) (Duarte 2012; Maertens 2014) for up to 28 days of total therapy. The primary endpoint of the trial was to assess average (C average) steady-state and trough-serum concentrations. Mean steady-state trough concentrations were greater than 1000 ng/mL, were achieved rapidly in patients administered the IV formulation, and were maintained at steady state, whereas slightly lower mean steady-state trough concentrations were observed in patients switched to the suspension at 400 mg twice daily (751 ng/mL) or 200 mg 3 times daily (950 ng/mL) (Cornely 2013). Intravenous posaconazole was well tolerated and had a similar safety profile similar to that of posaconazole oral suspension (Maertens 2014). However, the intravenous formulation must be administered through a central line because repeated infusions through a peripheral venous catheter are associated with high rates of infusion-site reactions (Merck 2014). Nevertheless, an initial dose can be administered through the peripheral vein catheter while waiting for central-line placement. Impact of New Posaconazole Formulations on Clinical Practice The introduction of a new delayed-release tablet and intravenous formulations of posaconazole provides important new options for the treatment of life-threatening invasive fungal diseases. Posaconazole has proven efficacy for invasive mold disease in high-risk patients and as a salvage therapy for invasive aspergillosis, yet a subset of the highest-risk patients could not achieve reliably effective blood levels with the oral suspension. The ability to start patients on an intravenous formulation, with transition to a more palatable and pharmacokinetically predictable delayed-release tablet that can be taken once daily, should significantly improve compliance and the probability of achieving and maintaining effective posaconazole blood levels (>1000 ng/mL) (Table 2). The suspension formulation should probably be reserved for patients who cannot take the tablet formulation. In theory, the introduction of these improved posaconazole formulations should lessen the need for therapeutic drug monitoring, although clinical experience with these newer formulations is still limited.

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Table 2. Summary of Posaconazole IV and Delayed-Release Tablet Pharmacokinetic Parameters [Geometric Mean (% CV) following a single-dose administration] (Data derived from US FDA 2014).

References

Cornely OA, Maertens J, Winston DJ, et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med. 2007; 356:348-359. Cornely OA, Haider S, Grigg A, et al. Phase 3 pharmacokinetics (PK) and safety study of posaconazole (POS) IV in patients (Pts) at risk for invasive fungal infection (IFI). Abstract 292. Presented at the 53rd International Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2013), Denver, Colorado, September 10-13, 2013. Dolton MJ, Ray JE, Chen SC-A, Ng K, Pont L, McLachlan AJ. Multicenter study of posaconazole therapeutic drug monitoring: exposure-response relationship and factors affecting concentration. Antimicrob Agents Chemother. 2012;56:5503-5510. Duarte RF, Lopez J, Cornely AO, Ma L, van Iersel M. Phase 1B study of the pharmacokinetics and safety of posaconazole solid oral tablets in patients at risk for invasive fungal infections. Abstract A-1934. Presented at the 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2012). San Francisco, California, September 9-12, 2012. Ezzet F, Wexler MD, Courtney R, Krishna G, Lim J, Laughlin M. Oral bioavailability of posaconazole in fasted healthy subjects. Clin Pharmacokinet. 2005;44:211-220. Kraft WK, Chang PS, van Iersel ML, et al. Posaconazole tablet pharmacokinetics: lack of effect of concomitant medications altering gastric pH and gastric motility in healthy subjects. Antimicrob Agents Chemother. 2014;58:4020-4025. Maertens J, Cornely OA, Ullmann AJ, et al. Pharmacokinetics and safety of posaconazole IV in patients at risk for invasive fungal disease: a phase 1B study. Antimicrob Agents Chemother. 2014;58:3610-3617.

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Merck Sharp & Dohme Corp (a subsidiary of Merci & Co, Inc.). Noxafil Package Insert. Whitehouse Station, New Jersey, 2014. Percival KM, Bergman SJ. Update on posaconazole pharmacokinetics: comparison of old and new formulations. Curr Fungal Infect Rep. 2014;8:139-145. Torres HA, Hachem RY, Chemaly RF, Kontoyiannis DP, Raad II. Posaconazole: a broad-spectrum triazole antifungal. Lancet Infect Dis. 2005;5:775-785. Ullmann AJ, Lipton JH, Vesole DH, et al. Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. N Engl J Med. 2007;356:335-347. United States Food and Drug Administration (US FDA). Noxafil tablets clinical pharmacology review [Internet]. 2014. Available at http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/UCM383684.pdf from: www.fda.gov Accessed July 1, 2014. Walsh TJ, Raad I, Patterson TF, et al. Treatment of invasive aspergillosis with posaconazole in patients who are refractory to or intolerant of conventional therapy: an externally controlled trial. Clin Infect Dis. 2007;44:2-12.

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Section 2: Antifungal Strategies Subsection 2a: IFI Strategies for Hematologic Malignancy Patients

Dimitrios Kontoyiannis, MD, ScD

Antifungal Risk Stratification and Prophylaxis in Hematologic Malignancy Patients Risk stratification and optimal antifungal strategies remain an art (Kontoyiannis 2011). A detailed knowledge of the “local” fungal epidemiology, the type of malignancy, and diagnostic strategies available to detect or screen for an IFI in a particular institution are all important for decision making regarding the optimal antifungal strategy, The net stage of immunosuppression is a rather complicated notion that is both semi-qualitative and semi-quantitative. Dose, duration, and sequence of immunosuppressive therapy; depth and duration of neutropenia; the number of episodes of neutropenia; and the presence of mucositis or metabolic issues (eg, diabetes or iron overload), are important factors affecting the net state of immunosuppression. Equally important are the presence of the immunosuppressive effects of herpes viruses, such as cytomegalovirus (CMV), a history of prior infection, and the antifungal selection pressure of prior or current antifungals (Freifeld 2011; Herbrecht 2012; Baden 2012). In our experience, old age, refractory leukemia or refractory GVHD, lack of neutrophil recovery, polymicrobial infection, poor performance status, and severe multiple comorbidities signify a host who is highly susceptible for developing a severe fungal infection, commonly presenting as significant pneumonia. To date, there has been a paucity of validated scorecards developed to assess fungal risk for the next stage of immunosuppression. Recently, hematologists at the University of Bologna proposed a clinical score (BOSCORE) that groups patients as at lower risk for IFIs (score <6, <1% risk) versus higher risk (score >6, >5% risk) (Stanzani 2013). If further replicated in other settings, a similar risk-assessment tool holds the promise to sharpen the assessment of the risk in intermediate-risk groups (eg, lymphomas) and avoid broad-spectrum antifungal prophylaxis in appropriately screened patients in other lower-risk groups. Whether or not host immunogenetics affecting the risk for infections owing to opportunistic pathogens such as fungi can add precision to clinical risk rules remains to be seen, but is an area of active investigation (Marr 2010; Kontoyiannis 2011). Based on pivotal randomized prospective studies in AML/MDS (Cornely 2007) and in patients with HSCT who had GVHD (Ullmann 2007), posaconazole is the preferred agent for primary prophylaxis for these conditions (as compared with fluconazole or itraconazole). This agent is endorsed by both the Infectious Diseases Society of America (IDSA) and the European Conference on Infections in Leukemia (ECIL) guidelines (A1 recommendation) (Freifeld 2011; Maertens 2011). This experience with the superior performance of posaconazole as prophylaxis has been also shown in real-life studies from University of Melbourne and MD Anderson Cancer Center (Ananda-Rajah 2012; Gomes 2014). The recent introduction of an extended release tablet as well as an intravenous formulation of posaconazole (with improved bioavailability) as well as the still-investigational triazole isavuconazole are expected to further increase the efficacy and options for azole-based antifungal prophylaxis (Krishna 2012; Maertens 2014; Pfaller 2013). Nevertheless, it is increasingly difficult to match a patient seen in the hospital with guidelines developed from prospective randomized trials. Drug interactions, prior antifungal exposures, gastrointestinal and renal function, pharmacokinetic concerns, drug dosing, as well as possibly fungal resistance are all factors that influence selection of an antifungal for primary or secondary prophylaxis. Furthermore, as most of the patients who develop a breakthrough IFI survive their initial episode and continue to have exposures to immunosuppressive drugs in an effort to achieve cure or control underlying disease, there is a need for continuation of antifungals as secondary prophylaxis. The strategy for secondary prophylaxis is not well worked out, in view of the paucity of an organized clinical experience. The limited studies available suggest that secondary antifungal prophylaxis with a triazole, such as voriconazole, appears to

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reduce the incidence of breakthrough invasive mold disease (Cordonnier 2010; Liu 2013). However, issues with long-term toxicities of antifungals need to be further investigated, including elevated risk of skin cancers and phototoxicity (Goval 2014; Feist 2012). Finally, it is important to remember the importance of emphasizing patient compliance to antifungal medications and avoidance of excessive environmental exposure to fungi to reduce the risk of developing an opportunistic fungal infection (Freifeld 2011; Kontoyiannis 2013; Ariza-Heredia 2014). Treatment Strategies for Invasive Fungal Infections in Patients With Hematological Malignancies: The Empirical (Fever-Driven) and Preemptive (Diagnostics-Driven) Approach Early and effective antifungal treatment is the cornerstone of the management of IFIs among patients with hematological malignancies and chemotherapy-induced neutropenia. Since fever may be the lone sign of an IFI, in the early 1980s, Pizzo et al. introduced the concept of the fever-driven, empirical antifungal therapy, aimed at treating occult IFIs before progression to overt disease (Pizzo 1982). In this setting, empirical antifungal therapy refers to the initiation of antifungal therapy in neutropenic patients with persistent fever despite 4 to 7 days of appropriate, broad-spectrum antibacterials or in those with relapsing, “biphasic” fever in the setting of persistent neutropenia (Cordonnier 2009). This strategy has been increasingly questioned because of 3 findings. First, there are multiple causes of fevers in neutropenic patients such as viruses, drugs or blood products, underlying malignancy, atypical pathogens (eg, Toxoplasma spp.), and increasingly multidrug resistant bacterial nosocomial pathogens (eg, vancomycin-resistant enterococci [VRE] and extended spectrum beta-lactamase-producing enterobacteriaceae) (Sipsas 2005; Freifeld 2011). In fact, only a minority of hematological patients meeting the criteria of empirical antifungal therapy has an actual IFI, and this percentage is getting smaller in the era of effective prophylaxis with broad-spectrum azoles (Maertens 2005). Second, increasingly, the high-resolution CT and non-culture-based diagnostics that detect fungal antigens in the serum, such as Aspergillus galactomannan (GM), (1–3)-β-D-glucan, or PCR, have high enough sensitivity to rule out early fungal infection, especially if serial tests are performed in high-risk patients (Freemantle 2011; Maertens 2005). Finally, most IFIs do not occur before about 10 days of profound neutropenia. Therefore, the guideline to begin empirical therapy after 4 to 7 days of persistent fever is questionable. Preemptive antifungal therapy has become an alternative to fever-driven, empiric use of antifungals. Although a standard definition is lacking, the term usually refers to more-targeted, less broad antifungal treatment of only those persistently febrile, neutropenic patients with additional findings suggestive of IFIs, such as serologic test results or chest CT findings but without definitive proof from histopathology or cultures. In a pivotal study, Maertens et al. showed the feasibility of a preemptive approach that incorporated these newer diagnostic tools into clinical practice as an alternative to empirical fever-driven therapy. In that particular study, empiric use of antifungal therapy was reduced by 78%, without compromising the safety of the patients. This approach allows for decreases in antifungal drug usage, thus reducing toxicity rates, costs, and possibly the emergence of resistance. Additionally, it allows the detection of afebrile patients with IFIs who are missed by a fever-driven empirical approach (Maertens 2005). However, it is unclear whether current diagnostics have sufficiently robust performance characteristics to justify the substitution of empiric antifungal approaches with more focused preemptive approaches. Outcomes vary from one study to another based on study design and patient characteristics. For example, in 2 randomized studies that compared preemptive and empirical strategies in neutropenic patients with hematological malignancies (1 involving serial PCR testing and 1 serial GM testing along with CT scans), no survival benefit was shown for the preemptive strategy vs the empirical strategy (Hebart 2009; Cordonnier 2009). Not surprisingly, the PCR-based, preemptive strategy led to the administration of antifungals to more patients compared with the empirical approach (Hebart 2009). In the PREVERT study, the IFI incidence was significantly higher in the preemptive group than in the empirical

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group (9% versus 3%), raising concerns regarding the safety of the preemptive approach (Cordonnier 2009). Pagano et al, in a prospective study using an electronic medical record system, examined the outcomes of empiric vs preemptive approaches in 397 “real-life,” febrile neutropenic patients with hematological malignancies and found that empirical antifungal treatment decreased the incidence of IFIs and attributable mortality compared with the preemptive antifungal approach (Pagano 2011). Preemptive approaches have also been compared with treatment guided by traditional diagnostics. An Australian study evaluated preemptive therapy guided by Aspergillus GM and PCR (biomarkers) vs therapy directed by traditional diagnostics (culture + histology) in high-risk hematology patients. They found that the use of biomarkers in a preemptive strategy reduced the number of patients who received antifungal therapy compared with that in the standard diagnosis group (17% difference, P=.002). While the biomarker-driven preemptive approach increased the number of probable and possible cases of aspergillosis, there was no difference between the groups in numbers of proven cases (Morrissey 2013). The latest IDSA guidelines on use of antimicrobial agents in neutropenic patients with cancer recommend empirical antifungal therapy and investigation for IFIs for high-risk patients with persistent or recurrent fever after 4 to 7 days of antibiotics and whose overall duration of neutropenia is expected to be >7 days (A-I recommendation). The guidelines considers the preemptive approach to be an acceptable alternative in febrile, neutropenic patients who are clinically stable (B-II) (Freifeld 2011). In contrast, the ECIL guidelines did not grade a recommendation for the preemptive strategy in hematological patients, considering it an experimental approach (Maertens 2011). Based on the sizeable body of published, multicenter randomized prospective studies (in which most patients were receiving fluconazole prophylaxis), both the IDSA and the ECIL recommend an echinocandin or a lipid formulation of amphotericin B (grade A1 recommendation from ECIL specifically for caspofungin and liposomal amphotericin B) for empiric antifungal treatment (Freifeld 2011; Maertens 2011; Walsh 2004). Most experts would agree that voriconazole would be an appropriate alternative (Freifeld 2011), although the study comparing voriconazole to liposomal amphotericin B failed to meet non-inferiority criteria (Walsh 2002). For patients receiving echinocandin-based prophylaxis, liposomal amphotericin B and voriconazole are recommended as first-line agents in the empiric setting. Echinocandin-based empirical therapy should not be used in centers with high prevalence of non-Candida yeasts (eg, Trichosporon spp.) or candidemia owing to echinocandin-resistant Candida strains (Kontoyiannis 2009). Finally, a minority (less than 5%) of patients who are on prophylaxis with a broad-spectrum azole (posaconazole, voriconazole) will develop a breakthrough IFI (Lerolle 2011; Gomes 2014). In these patients, careful attention to the workup of the nature of fever, an early use of sinus/chest CT, and knowledge of the local epidemiology are important. For example, at MD Anderson Cancer Center, because of the high prevalence of non-Aspergillus molds and mixed mold infections, liposomal amphotericin B remains the mainstay of empiric/preemptive antifungal choices in patients with presumed early fungal pneumonia. The optimal duration of empirical antifungal treatment has not been well established. If neutropenia has resolved and the patient is afebrile for at least 3 days and clinically stable without a documented IFI, then antifungal administration can be discontinued. If neutropenia persists, the patient remains afebrile, and if a meticulous repeat clinical and laboratory workup shows no symptoms or signs of fungal infection, then antifungal administration can be stopped after 2 weeks. In our opinion, in clinically stable patients with persistent fever despite the resolution of neutropenia and if a careful reassessment for IFIs is negative, then antifungals can be discontinued and other causes for the fever should be sought. On the other hand, in clinically unstable patients with persistent fever and/or neutropenia, empirical antifungal treatment should be continued until resolution of both fever and neutropenia (Sipsas 2005). For preemptive antifungal therapy, treatment for at least 3 weeks and reassessment of clinical and radiological responses are the first step. In the responding patients, especially if the patient is in complete hematologic remission, then step-down therapy with an oral extended spectrum triazole is reasonable. For the patient who does not respond within 7 to 10 days who has a presumed fungal pneumonia and has started on a preemptive regimen, individualized decisions are required. Most options available at this stage have not been studied rigorously in a prospective fashion. In such situations, we would typically

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repeat the workup in an effort to establish the diagnosis, change the antifungal to an agent that belongs to another class, “stage” the disease with the use of repeat CT, and consider combination therapy or immune adjunct therapy for selected patients (Figure 1).

References Ananda-Rajah MR, Grigg A, Downey MT, et al. Comparative clinical effectiveness of prophylactic voriconazole/posaconazole to fluconazole/itraconazole in patients with acute myeloid leukemia/myelodysplastic syndrome undergoing cytotoxic chemotherapy over a 12-year period. Haematologica. 2012;97:459-463. Ariza-Heredia EJ, Kontoyiannis DP. Our recommendations for avoiding exposure to fungi outside the hospital for patients with haematological cancers. Mycoses. 2014;57:336-341. Baden LR, Bensinger W, Angarone M, et al; National Comprehensive Cancer Network. Prevention and treatment of cancer-related infections. J Natl Compr Canc Netw. 2012;10:1412-1445. Cordonnier C, Pautas C, Maury S, et al. Empirical versus preemptive antifungal therapy for high-risk patients with febrile neutropenia: a randomized, controlled trial. Clin Infect Dis. 2009;48:1042-1051. Cornely OA, Maertens J, Winston DJ, et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med. 2007;356:348-359. Feist A, Lee R, Osborne S, Lane J, Yung G. Increased incidence of cutaneous squamous cell carcinoma in lung transplant recipients taking long-term voriconazole. J Heart Lung Transplant. 2012;31:1177-1181. Freemantle N, Tharmanathan P, Herbrecht R. Systematic review and mixed treatment comparison of randomized evidence for empirical, pre-emptive and directed treatment strategies for invasive mould disease. J Antimicrob Chemother. 2011;66 (Suppl 1):i25-i35.

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Freifeld AG, Bow EJ, Sepkowitz KA, et al; Infectious Diseases Society of America. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2011;52:427-431. Gomes MZ, Jiang Y, Mulanovich VE, Lewis RE, Kontoyiannis DP. Effectiveness of primary anti-Aspergillus prophylaxis during remission induction chemotherapy of acute myeloid leukemia. Antimicrob Agents Chemother. 2014;58:2775-2780. Goyal RK, Gehris RP, Howrie D, Cogley KM, Windreich RM, Venkataramanan R. Phototoxic dermatoses in pediatric BMT patients receiving voriconazole. Pediatr Blood Cancer. 2014;61:1325-1328. 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. Herbrecht R, Bories P, Moulin JC, Ledoux MP, Letscher-Bru V. Risk stratification for invasive aspergillosis in immunocompromised patients. Ann N Y Acad Sci. 2012;1272:23-30. Kontoyiannis DP. Echinocandin-based initial therapy in fungemic patients with cancer: a focus on recent guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2009;49:638-639. Kontoyiannis DP. Antifungal prophylaxis in hematopoietic stem cell transplant recipients: the unfinished tale of imperfect success. Bone Marrow Transplant. 2011;46:165-173. Kontoyiannis DP. Preventing fungal disease in chronically immunosuppressed outpatients: time for action? Ann Intern Med. 2013;158:555-556. Krishna G, Ma L, Martinho M, O'Mara E. Single-dose phase I study to evaluate the pharmacokinetics of posaconazole in new tablet and capsule formulations relative to oral suspension. Antimicrob Agents Chemother. 2012;56:4196-4201. Lerolle N, Raffoux E, Socie G, et al. Breakthrough invasive fungal infections (IFI) in patients treated with posaconazole as primary prophylaxis: a four year study. Clin Microbiol Infect. 2014. doi:10.1111/1469-0691.12688. Liu F, Wu T, Wang JB, et al. Risk factors for recurrence of invasive fungal infection during secondary antifungal prophylaxis in allogeneic hematopoietic stem cell transplant recipients. Transpl Infect Dis. 2013;15:243-250. Maertens J, Marchetti O, Herbrecht R, et al; Third European Conference on Infections in Leukemia. European guidelines for antifungal management in leukemia and hematopoietic stem cell transplant recipients: summary of the ECIL 3--2009 update. Bone Marrow Transplant. 2011;46:709-718. Maertens J, Theunissen K, Verhoef G, et al. Galactomannan and computed tomography–based preemptive antifungal therapy in neutropenic patients at high risk for invasive fungal infection: a prospective feasibility study. Clin Infect Dis. 2005;41:1242-1250. Maertens J, Cornely OA, Ullmann AJ, et al. Phase 1B study of the pharmacokinetics and safety of posaconazole intravenous solution in patients at risk for invasive fungal disease. Antimicrob Agents Chemother. 2014;58:3610-3617. Marr KA. Fungal infections in oncology patients: update on epidemiology, prevention, and treatment. Curr Opin Oncol. 2010;22:138-142. Morrissey CO, Chen SC, Sorrell TC, et al; Australasian Leukaemia Lymphoma Group and the Australia and New Zealand Mycology Interest Group. Galactomannan and PCR versus culture and

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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. Pagano L, Caira M, Nosari A, et al; HEMA e-Chart Group. The use and efficacy of empirical versus pre-emptive therapy in the management of fungal infections: the HEMA e-Chart Project. Haematologica. 2011;96:1366-1370. Pfaller MA, Messer SA, Rhomberg PR, Jones RN, Castanheira M. In vitro activities of isavuconazole and comparator antifungal agents tested against a global collection of opportunistic yeasts and molds. J Clin Microbiol. 2013;51:2608-2616. 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. Sipsas NV, Bodey GP, Kontoyiannis DP. Perspectives for the management of febrile neutropenic patients with cancer in the 21st century. Cancer. 2005;103:1103-1113. Stanzani M, Lewis RE, Fiacchini M, et al. A risk prediction score for invasive mold disease in patients with hematological malignancies. PLoS One. 2013;8:e75531. Ullmann AJ, Lipton JH, Vesole DH, et al. Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. N Engl J Med. 2007;356:335-347. Walsh TJ, Finberg RW, Arndt C, et al; National Institute of Allergy and Infectious Diseases Mycoses Study Group. Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. N Engl J Med. 1999;340:764-771. Walsh TJ, Pappas P, Winston DJ, et al. Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. N Engl J Med. 2002;346:225-234. Walsh TJ, Teppler H, Donowitz GR, et al. Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia. N Engl J Med. 2004;351:1391-1402.

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Section 2: Antifungal Strategies

Subsection 2b. Risk Stratification and Management of Invasive Candidiasis

Dimitrios Kontoyiannis, MD, ScD

Epidemiologic Considerations in IC Invasive candidiasis (IC) remains a major cause of morbidity and mortality among immunosuppressed and critically ill patients. Epidemiologic trends in IC reflect advances in supportive care and resulting increased survival rates in high-risk patients susceptible to this infection (Pappas 2009). It should be noted that IC can occur without candidemia; in a recent multicenter study in French ICUs, 32.1% of patients had IC without documented candidemia (Leroy 2009).

Patients with IC have multiple, interrelated risk factors for IC (Table 1), such as prior use of broad-spectrum antibiotics; placement of central venous catheters (CVCs) and/or nasogastric tubes; receipt of total parenteral nutrition (TPN); advanced age; diabetes mellitus; use of immunosuppressive agents including corticosteroids; use of gastric acid suppressants; prior abdominal surgery, especially when complicated by gastrointestinal tract perforations and anastomotic leaks; advanced underlying illness; Candida species colonization, especially when isolated from multiple sites; and length of ICU stay greater than 7 days (Pappas 2009; Chow 2008; Leroy 2009; Blumberg 2001; Pittet 1994). Patients with cancer have additional risk factors for candidemia, such as chemotherapy-induced neutropenia and/or mucositis, treatment with systemic corticosteroids, radiation therapy, HSCT and subsequent GVHD, and tumors that disrupt mucosal integrity (Slavin 2010; Sipsas 2009).

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IC incidence increased over the last decades, especially in ICUs, with a shift in the distribution of Candida spp., from C. albicans to non-albicans Candida spp. such as C. glabrata, C. tropicalis, C. krusei, and C. parapsilosis (Slavin 2010; Sipsas 2009; Leroy 2010). Several risk factors for IC caused by non-albicans Candida spp. have been reported, including prior fluconazole use, prior use of broad-spectrum antibacterials, history of gastrointestinal surgery, and CVC placement (Chow 2008; Slavin 2010; Playford 2008; Holley 2009). However, whether there are distinct clinical factors separating patients infected with C. albicans from those infected with non-albicans Candida spp. is unclear. The adoption of azole prophylaxis has resulted in increasing incidences of breakthrough candidemias, typically from non-albicans Candida spp., such as C. glabrata and C. krusei (Chow 2008). The incidence of breakthrough catheter-related candidemias caused by C. parapsilosis has increased in patients receiving echinocandins (Trofa 2008).

IC is a major cause of direct or indirect mortality in both immunocompetent and immunosuppressed critically ill patients—crude and attributable mortality rates range from 40% to 78%, and from 20% to 40%,

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respectively (Slavin 2010; Dimopoulos 2007). It is difficult to ascribe “attributable” mortality in IC without performing an autopsy, as IC is a “marker” of severe, debilitating illness (Zaoutis 2005). Infections with different Candida spp. have different mortality rates. For example, in the Prospective Antifungal Therapy Alliance database (2496 patients), infections with multiple non-C. albicans had the lowest survival rate (53.1%), whereas infections with C. parapsilosis and C. lusitaniae had the highest survival rates (70.7% and 74.5%, respectively). Survival rates for patients infected with C. glabrata, C. tropicalis, C. krusei, C. guilliermondii, and C. dublinensis were intermediate and similar, ranging from 57.7% for C. krusei to 61.4% for C. dublinensis (Pfaller 2014). A recent meta-analysis of 7 randomized treatment trials in 1895 patients with IC-identified infection with C. tropicalis as predictive of mortality (Andes 2012). It is noteworthy that in clinical trials of new antifungal agents, mortality rates were substantially lower, most likely reflecting patient selection and exclusion of patients with cancer rather than better efficacy of the newer agents (Kullberg 2005; Kuse 2007; Reboli 2007). In fact, real-life studies highlight the persistence of high mortality rates for infections with Candida spp., especially in the ICU (Lortholary 2014).

Diagnostic Challenges Timely diagnosis of IC remains a challenge. Conventional blood culture systems are relatively insensitive (<50% sensitivity), particularly in the setting of pre-existing antifungal therapy, and typically take several days to become positive. In addition, identification of a Candida at the species level and delineation of its sensitivity to available antifungal agents may take an additional 48 hours. Because of delays in the diagnosis of frequently lethal IC, efforts have focused on developing non-culture-based diagnostic methods, such as detection of fungal nucleic acids, antibodies, and cell wall components, such as mannan, galactomannan, and the “pan-fungal” marker (1,3)-β-D-glucan (BG) (Sendid 2002; Ostrosky-Zeichner 2005). A meta-analysis of studies evaluating assays for detection of BG in serum yielded a pooled sensitivity rate of 76.8% and specificity rate of 85.3%. Importantly, BG–based assays detect culture-negative IC arising from an intra-abdominal source. The most useful characteristic of these tests is their excellent negative predictive values, which can help rule out IC (Karageorgopoulos 2011).

Molecular diagnostic tests used to detect Candida spp. DNA in blood or tissue specimens are investigational, and how useful they are in ICU patients is unclear. These non–culture-based diagnostics are expected to increasingly be introduced in the diagnosis of IC. A recent single institution study simulated time to initiation of antifungal therapy with rapid diagnostics and showed 0.6 ± 0.2 days for T2Candida, 2.6 ± 1.3 days for PNA-FISH, and 2.5 ± 1.4 days for matrix-assisted laser desorption/ionization time of flight. In this study, use of T2Candida on the day of blood culture turning positive was projected to result in 3136 to 6078 fewer doses of echinocandins annually per 5000 patients (Aitken 2014). It will be important to validate these molecular measures. As mentioned previously, establishing sensitivity for IC diagnostics is difficult given the lack of appropriate “gold standard” controls, as autopsy rates in ICU patients are very low.

Diagnosing CVC-Related Candidemia Use of CVCs, an essential component of the modern care of critically ill patients, could serve as a nidus for candidemia. Catheter-related candidemia can be diagnosed by the following criteria: 1) no other apparent source of the infection, 2) the same Candida spp. is isolated from both peripheral blood and catheter-tip cultures (≥15 colony-forming units, analyzed using a semiquantitative method), and 3) a quantitative blood culture collected via a CVC with at least 5-fold more colony-forming units per mm3 than in a concurrently obtained peripheral blood culture (Antoniadou 2003; Raad 2004a; Raad 2004b). A sensitive but nonspecific marker for CVC-related candidemia is the time needed to detect Candida spp. in peripheral blood cultures (time to positivity). A time to positivity greater than 30 hours can help exclude an intravascular catheter as the source of candidemia (Ben-Ami 2008). Assessing Risk Timely diagnosis of IC remains a challenge, despite the introduction of newer techniques. Delayed initiation of antifungal therapy is associated with increased mortality (Garey 2006). Therefore, prediction rules have been developed and validated prospectively, to identify those patients at high risk for IC and likely to benefit from early treatment, especially in the ICU setting. Researchers have used host risk

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factors and/or Candida spp. colonization to create clinically relevant scores to help in this process (Ostrosky-Zeichner 2007). They developed prediction rules for IC addressing only clinical risk factors, such as mechanical ventilation, use of broad-spectrum antibiotics, placement of a CVC, use of TPN, diabetes mellitus, use of dialysis, history of major surgery, pancreatitis, and use of corticosteroids or other immunosuppressive agents (Paphitou 2005; Ostrosky-Zeichner 2011; Ostrosky-Zeichner 2007). Hermsen and colleagues conducted a matched, case-controlled validation and comparison of these predictive rules for IC in the ICU as shown in Table 2. Based on low positive predictive values (PPVs) and high negative predictive values (NPVs), the authors concluded that the rules are most helpful for identifying patients who are not likely to develop IC (Hermsen 2011). Similarly, in a prospective multicenter study of a cohort of Australian ICU patients, the Ostrosky-Zeichner clinical predictive rule was validated but showed poorer performance; however, the performance improved markedly with the post-hoc addition of colonization parameters (Playford 2009).

Inclusion of colonization information may increase the utility of these rules. In a pivotal study, Pittet et al developed the colonization index (CI), which is the number of distinct body sites colonized by Candida spp. divided by the total number of distinct sites tested per patient. To increase the sensitivity and specificity of the CI, these authors proposed a corrected CI: the CI multiplied by the ratio of the number of body sites with heavy colonization (as assessed using semiquantitative cultures) to the total number of sites with growing Candida spp. The threshold for initiation of preemptive antifungal therapy was set at a CI of at least 0.5 or corrected CI of at least 0.4 (Pittet 1994). These data underline the complementary contribution of clinical risk factors and Candida spp. colonization to risk-prediction models. Spanish investigators adopted this approach of combining clinical and colonization factors, proposing the use of a “Candida score” based on strong clinical predictors of IC, such as history of surgery, use of TPN, and severe sepsis along with multisite Candida colonization. Patients who had Candida scores higher than 2.5 benefited from early treatment. The researchers validated this finding in a prospective study, which confirmed that IC development is highly improbable in patients with colonization and Candida scores <3 (León 2009). However, while these prediction rules were developed for ICU candidiasis, they have not been validated in patients with cancer or other types of immunosuppression, because all of the relevant studies excluded neutropenic patients.

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IC Management Strategies Early (empirical or preemptive) therapy for IC. Results of several retrospective studies have shown that reduced times to treatment of IC correlate with reduced mortality rates (Garey 2006). Therefore, early treatment (ie, before positive blood cultures) in patients at high risk for IC is common (Golan 2005). Empirical antifungal-based treatment is considered for a patient with a febrile illness of no apparent cause that is not responding to treatment with broad-spectrum antibiotics. Preemptive therapy is a strategy in which antifungal treatment is deferred until clinicians obtain substantial evidence of the presence of IC, such as infection-positive serological markers and imaging findings. A recent prospective randomized study showed that early, preemptive therapy for IC based on a positive BG test reduced the incidence but not the mortality of candidemia in ICU patients (Piarroux 2004). Regarding empirical therapy for IC, a randomized multicenter, double-blinded, placebo-controlled trial showed that empirical treatment with fluconazole in ICU patients did not improve clinical outcomes (Schuster 2008). However, in that study, many low-risk patients were enrolled, not allowing an appropriate estimation of the protective effect of fluconazole.

Treatment of documented IC. The selection of the initial antifungal regimen for IC should be guided by the local epidemiology of Candida spp., prior azole exposure, history of intolerance to a particular antifungal agent, acuteness and severity of the IC, comorbidities, possible interactions with other drugs, and suspicion or evidence of involvement of the eye, central nervous system (CNS), artificial cardiac valves, and/or visceral organs (Pappas 2009). Also, in vitro susceptibility data should be interpreted cautiously, since they provide no “real-time” information for the management of patients in the first crucial hours of IC. Notably, no studies have proved their usefulness in guidance of antifungal therapy (Sipsas 2009; Kontoyiannis 2009).

The hemodynamic status of the patient and his/her prior exposure to antifungals are important criteria for selection of initial antifungal therapy. Thus, fluconazole is used for IC in hemodynamically stable patients with no history of azole exposure and no other risk factors for poor outcome. Typically, patients with cancer, especially those with hematological malignancies, do not meet this criterion. The typical fluconazole dosing schedule is a loading dose of 800 mg followed by 400 mg daily; ideally the fluconazole dose should be based on actual body weight (mg/kg), especially in obese patients who might otherwise be underdosed (Pittrow 1999). Therapy with an echinocandin (eg, caspofungin at a loading dose of 70 mg then 50 mg daily, micafungin at 100 mg daily, anidulafungin at a loading dose of 200 mg then 100 mg daily) is preferred in hemodynamically unstable patients with recent azole exposure, immunosuppression, or comorbidities or at high risk for infections with non-albicans Candida spp., especially C. krusei and C. glabrata (Pappas 2009). A recent patient-level analysis drawn from 7 randomized treatment trials in patients with IC suggested that echinocandin-based treatment is an independent predictor for improved survival and clinical success (Andes 2012). Echinocandin use should be avoided in patients with CNS or urinary tract infections or endophthalmitis because of poor drug penetration in these sites. For patients who have initially received an echinocandin, transition to fluconazole (ie, treatment de-escalation) is recommended if they are clinically improved (Pappas 2009). Voriconazole (6 mg/kg given twice daily for 2 doses then 3 to 4 mg/kg given twice daily), although effective against IC (Kullberg 2005), is a less attractive first-line agent because of disadvantages such as twice-daily dosing and variability in blood levels.

The necessity of and timing of CVC removal in candidemic patients, especially those with cancer and/or neutropenia, are controversial (Nucci 2002; Nucci 2010; Pappas 2009; Raad 2004b). Some published studies suggested that early removal of CVC (ie, <48 hours after onset of candidemia) is associated with reduced mortality rates (Raad 2004b), but other analyses do not show a benefit (Nucci 2010). A recent meta-analysis of 7 randomized trials of treatment of IC showed that CVC removal improved survival and clinical outcomes independently of disease severity or infecting Candida species (Andes 2012). However, in cancer patients, other sources—such as the gastrointestinal tract—may be the source of candidemia rather than the central catheter (Anaissie 1998; Nucci 2001; Raad 2004b). Well-designed, prospective, randomized trials with CVC management as the primary end point are required to address the benefits of CVC removal in cancer patients. Use of antifungal locks may be considered as catheter salvage therapy when catheter removal is not logistically feasible (Raad 2008). Another aspect of management of IC is

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surveillance for Candida endophthalmitis. The current recommendation is that all patients with candidemia should receive a dilated ophthalmologic evaluation to exclude Candida endophthalmitis. Neutropenic patients may not manifest visible endophthalmitis until recovery from neutropenia, and therefore the examination should be performed after recovery of the neutrophil count (Pappas 2009).

The IC treatment should be continued for at least 2 weeks after clearance of Candida spp. from the bloodstream and resolution of all symptoms and signs of systematic or focal infection (Pappas 2009). Failure to control IC despite appropriate antifungal-based treatment, typically resulting from a persistent focus of infection with resistant Candida spp. or prolonged immune suppression, is associated with high mortality rates. Therapeutic options in such cases are limited and of questionable efficacy. They include salvage therapy with a new antifungal (Ostrosky-Zeichner 2003), increased dosing of an appropriate antifungal (Rex 2003), combination therapy (Sobel 2004), and/or adjunct immunotherapy (Kullberg 2004).

Unfortunately, major clinical studies on the efficacy of newer antifungals typically do not include very ill patients such as those with multiple morbidities or cancer. Despite the introduction of more efficient and less toxic antifungals, crude and attributable mortality of IC among high-risk patients remains high (Slavin 2010). Surveillance for documented IFIs in the ICUs and implementation of infection control protocols are of paramount importance.

Despite the introduction of new antifungal agents with improved activity and reduced toxicity, mortality rates for IC remain high, especially in ICU patients and those with a rapidly advancing underlying disease. The goals in the future include close monitoring of the ever-changing epidemiology of IC; refinement of existing risk-stratification models; and development of novel, highly sensitive, specific diagnostic tools for early detection of infection, thus allowing a preemptive rather than empiric therapeutic approach; development of more effective, less toxic antifungals; development of new therapeutic and prophylactic protocols; use of prognostic biomarkers for treatment efficacy monitoring; and implementation of antifungal stewardship programs.

References Aitken SL, Beyda ND, Shah DN, et al. Clinical practice patterns in hospitalized patients at risk for invasive candidiasis: role of antifungal stewardship programs in an era of rapid diagnostics. Ann Pharmacother. 2014;48:683-690.

Anaissie EJ, Rex JH, Uzun O, Vartivarian S. Predictors of adverse outcome in cancer patients with candidemia. Am J Med. 1998;104:238-245.

Andes DR, Safdar N, Baddley J, et al. Impact of treatment strategy on outcomes in patients with candidemia and other forms of invasive candidiasis: a patient-level quantitative review of randomized trials. Clin Infect Dis. 2012;54:1110-1122.

Antoniadou A, Torres HA, Lewis RE, et al. Candidemia in a tertiary care cancer center: in vitro susceptibility and its association with outcome of initial antifungal therapy. Medicine. 2003;82:309-321.

Ben-Ami R, Weinberger M, Orni-Wasserlauff R, et al. Time to blood culture positivity as a marker for catheter-related candidemia. J Clin Microbiol. 2008;46:2222-2226.

Blumberg HM, Jarvis WR, Soucie JM, et al. Risk factors for candidal bloodstream infections in surgical intensive care unit patients: the NEMIS prospective multicenter study. Clin Infect Dis. 2001;33:177-186.

Chow JK, Golan Y, Ruthazer R, et al. Factors associated with candidemia caused by non-albicans Candida species versus Candida albicans in the intensive care unit. Clin Infect Dis. 2008;46:1206-1213.

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Dimopoulos G, Karabinis A, Samonis G, Falagas ME. Candidemia in immunocompromised and immunocompetent critically ill patients: a prospective comparative study. Eur J Clin Microbiol Infect Dis. 2007;26:377-384.

Garey KW, Rege M, Pai MP, et al. Time to initiation of fluconazole therapy impacts mortality in patients with candidemia: a multi-institutional study. Clin Infect Dis. 2006;43:25-31.

Golan Y, Wolf MP, Pauker SG, Wong JB, Hadley S. Empirical anti-Candida therapy among selected patients in the intensive care unit: a cost-effectiveness analysis. Ann Intern Med. 2005;143:857-869.

Hermsen ED, Zapapas MK, Maiefsky M, Rupp ME, Freifeld AG, Kalil AC. Validation and comparison of clinical prediction rules for invasive candidiasis in intensive care unit patients: a matched case-control study. Critical Care. 2011;15:R198.

Holley A, Dulhunty J, Blot S, et al. Temporal trends, risk factors and outcomes in albicans and non-albicans candidaemia: an international epidemiological study in four multidisciplinary intensive care units. Int J Antimicrob Agents. 2009;33:554.e1-7.

Karageorgopoulos DE, Vouloumanou EK, Ntziora F, Michalopoulos A, Rafailidis PI, Falagas ME. β-d-Glucan assay for the diagnosis of invasive fungal infections: a meta-analysis. Clin Infect Dis. 2011;52:750-770.

Kontoyiannis DP. Echinocandin-based initial therapy in fungemic patients with cancer: a focus on recent guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2009;49:638-639.

Kullberg BJ, Oude Lashof AM, Netea MG. Design of efficacy trials of cytokines in combination with antifungal drugs. Clin Infect Dis. 2004;39(Suppl 4):S218-S223.

Kullberg BJ, Sobel JD, Ruhnke M, et al. Voriconazole versus a regimen of amphotericin B followed by fluconazole for candidaemia in non-neutropenic patients: a randomised non-inferiority trial. Lancet. 2005;366:1435-1442.

Kuse ER, Chetchotisakd P, da Cunha CA, et al. Micafungin versus liposomal amphotericin B for candidaemia and invasive candidosis: a phase III randomized double-blind trial. Lancet. 2007;369:1519-1527.

León C, Ruiz-Santana S, Saavedra P, 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;37:1624-1633.

Leroy O, Gangneux JP, 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;37:1612-1618.

Leroy O, Mira JP, Montravers P, Gangneux JP, Lortholary O; AmarCand Study Group. Comparison of albicans vs. non-albicans candidemia in French intensive care units. Crit Care. 2010;14:R98.

Lortholary O, Renaudat C, Sitbon K, et al; The French Mycosis Study Group. Worrisome trends in incidence and mortality of candidemia in intensive care units (Paris area, 2002-2010). Intensive Care Med. 2014 Aug 6. [Epub ahead of print].

Nucci M, Anaissie E. Revisiting the source of candidemia: skin or gut? Clin Infect Dis. 2001;33:1959-1967.

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Nucci M, Anaissie E. Should vascular catheters be removed from all patients with candidemia? An evidence-based review. Clin Infect Dis. 2002;34:591-599.

Nucci M, Anaissie E, Betts RF, et al. Early removal of central venous catheter in patients with candidemia does not improve outcome: analysis of 842 patients from 2 randomized clinical trials. Clin Infect Dis. 2010;51:295-303.

Ostrosky-Zeichner L, Alexander BD, Kett DH, 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;41:654-659.

Ostrosky-Zeichner L, Oude Lashof AM, Kullberg BJ, Rex JH. Voriconazole salvage treatment of invasive candidiasis. Eur J Clin Microbiol Infect Dis. 2003;22:651-655.

Ostrosky-Zeichner L, Pappas PG, Shoham S, et al. Improvement of a clinical prediction rule for clinical trials on prophylaxis for invasive candidiasis in the intensive care unit. Mycoses. 2011;54:46-51.

Ostrosky-Zeichner L, Sable C, Sobel J, 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;26:271-276.

Paphitou NI, Ostrosky-Zeichner L, Rex JH. Rules for identifying patients at increased risk for candidal infections in the surgical intensive care unit: approach to developing practical criteria for systematic use in antifungal prophylaxis trials. Med Mycol. 2005;43:235-243.

Pappas PG, Kauffman CA, Andes D, et al. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis. 2009;48:503-535.

Pfaller MA, Andes DR, Diekema DJ, et al. Epidemiology and outcomes of invasive candidiasis due to non-albicans species of Candida in 2,496 patients: data from the Prospective Antifungal Therapy (PATH) Registry 2004-2008. PLoS One. 2014;9(7):e101510.

Piarroux R, Grenouillet F, Balvay P, et al. Assessment of preemptive treatment to prevent severe candidiasis in critically ill surgical patients. Crit Care Med. 2004;32:2443-2449.

Pittet D, Monod M, Suter PM, et al. Candida colonization and subsequent infections in critically ill surgical patients. Ann Surg. 1994;220:751-758.

Pittrow L, Penk A. Special pharmacokinetics of fluconazole in septic, obese and burn patients. Mycoses. 1999;42(Suppl 2):87-90.

Playford EG, Lipman J, Kabir M, et al. Assessment of clinical risk predictive rules for invasive candidiasis in a prospective multicentre cohort of ICU patients. Intensive Care Med. 2009;35:2141-2145.

Playford EG, Marriott D, Nguyen Q, et al. Candidemia in nonneutropenic critically ill patients: risk factors for non-albicans Candida spp. Crit Care Med. 2008;36:2034-2039.

Raad II, Hachen RY, Hanna HA, et al. Role of ethylene diamine tetra-acetic acid (EDTA) in catheter lock solutions: EDTA enhances the antifungal activity of amphotericin B lipid complex against Candida embedded in biofilm. Int J Antimicrob Agents. 2008;32:515-518.

aRaad I, Hanna HA, Alakech B, Chatzinikolaou I, Johnson MM, Tarrand J. Differential time to positivity: a useful method for diagnosing catheter-related bloodstream infections. Ann Intern Med. 2004;140:18-25.

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bRaad I, Hanna H, Boktour M, et al. Management of central venous catheters in patients with cancer and candidemia. Clin Infect Dis. 2004;38:1119-1127.

Reboli AC, Rotstein C, Pappas PG, et al. Anidulafungin versus fluconazole for invasive candidiasis. N Engl J Med. 2007;356:2472-2482.

Rex JH, Pappas PG, Karchmer AW, et al; National Institute of Allergy and Infectious Diseases Mycoses Study Group. 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;36:1221-1228.

Schuster MG, Edwards JE Jr, Sobel JD, et al. Empirical fluconazole versus placebo for intensive care unit patients: a randomized trial. Ann Intern Med. 2008;149:83-90.

Sendid B, Poirot JL, Tabouret M, 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;51:433-442.

Sipsas NV, Kontoyiannis DP. Invasive fungal infections in patients with cancer in the intensive care unit. Int J Antimicrob Agents. 2012;39. doi:10.1016/j.ijantimicag.2011.11.017.

Sipsas NV, Lewis RE, Tarrand J, et al. Candidemia in patients with hematologic malignancies in the era of new antifungal agents (2001-2007): stable incidence but changing epidemiology of a still frequently lethal infection. Cancer. 2009;115:4745-4752.

Slavin MA, Sorrell TC, Marriott D, et al. Candidaemia in adult cancer patients: risks for fluconazole-resistant isolates and death. J Antimicrob Chemother. 2010;65:1042-1051.

Sobel JD. Combination therapy for invasive mycoses: evaluation of past clinical trial designs. Clin Infect Dis. 2004;39(Suppl 4):S224-S227.

Trofa D, Gácser A, Nosanchuk JD. Candida parapsilosis, an emerging fungal pathogen. Clin Microbiol Rev. 2008;21:606-625.

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Section 2: Antifungal Strategies Subsection 2c: Incorporating Antifungal Stewardship Into Practice Russell E. Lewis, PharmD

Background Institutional antimicrobial stewardship programs have traditionally focused on antibacterials because of significant burden of resistance to these agents and its impact on hospital-acquired infections. Nevertheless, antifungal therapy has a tremendous impact on patient outcomes when used appropriately but also carries significant risk to patients (eg, toxicities, drug interactions) when prescribed inappropriately (Ananda-Rajah 2012). Moreover, antifungal resistance is an increasing, but often under-recognized problem, as illustrated by recent reports of increasing multidrug- and echinocandin-resistant Candida glabrata (Alexander 2013; Beyda 2014; Pham 2014) and emerging multi-triazole resistance among Aspergillus spp. (Warris 2002).

Use of systemic antifungal therapy is concentrated in the critically ill, transplant, and hematology-oncology patient populations. Mortality rates for invasive candidiasis and mold diseases remain substantial, and inadequately treated fungal infections prolong ICU stays or delay potentially curative chemotherapy, resulting in poorer long-term patient prognosis (Bow 1995; Girmenia 2014). Nevertheless, the continued high mortality rate of these infections and limited sensitivity of current diagnostic tools for fungal pathogens are major factors that drive the overuse of antifungal agents (Ananda-Rajah 2012).

Essential Elements and Key Strategies of Antifungal Stewardship Program Multiple factors can influence the success of an antifungal stewardship program. Ananda-Rajah, Slavin, and Thursky (Ananda-Rajah 2012) have proposed 3 essential elements and 4 key strategies that should be considered in developing any prospective program that will promote effective use of systemic antifungal agents (Table 1).

Key Elements Practice guidelines have been described as a cornerstone for developing an antifungal stewardship program (Ananda-Rajah 2012), but are rarely applied in routine clinical care unless they are available in a

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point-of-care fashion at the same time as drug prescribing and ordering of diagnostic tests. Many national and international guidelines are available for invasive fungal infections, but were derived primarily from non-inferiority drug registration trials that excluded patients with organ dysfunction or poor underlying disease prognosis (Herbrecht 2012). Consequently, guidelines must be individualized to the specific epidemiology of the institution and type of patients that are actually being treated in the institution.

Restriction and pre-prescription approval are a common component of many stewardship programs, but such restrictions must be designed in a fashion that avoids unintended patient harm because of delay in effective antifungal therapy—a factor repeatedly shown to be a risk factor for increased risk of death from fungal infections (Morrell 2005; Garey 2006; Greene 2007). Most institutions have employed web-based approval systems or requests made at the time of order entry that allow doctors to obtain approval for guideline-acceptable or non-guideline acceptable prescriptions. Typically, doses for the first 48 to 72 hours may be dispensed pending review by an infectious diseases physician or stewardship team member. Importantly, post-prescription review and feedback is essential to improve communication and build trust with prescribers.

Two areas of antifungal use in particular are often initially targeted in antifungal stewardship programs. Empiric antifungal therapy has been estimated to account for about two thirds of inpatient antifungal prescribing (Pagano 2009; Des Champs-Bro 2011) but is often continued for extended periods even in the absence of evidence of a fungal infection. The second area of antifungal use that should be addressed is patterns of antifungal prophylaxis (ie, voriconazole or posaconazole) in high-risk populations. When initiating a new stewardship program, it is common to initially concentrate on a few “problem drugs” used for these infections rather than control all antifungal use in the hospital. Initially concentrating on a few areas provides greater opportunity for “easy wins” in key prescribing areas that are essential for advancing administrative and senior physician support of the program.

Key Program Strategies Restraining empiric antifungal use and de-escalation of empiric antifungal therapy are 2 of the most difficult prescribing practices to modify. Both modifications dictate that physicians have some confidence in current antifungal diagnostic tools and are in agreement on which populations or patients are at sufficient risk for invasive fungal infection to justify therapy. Unfortunately, blood and respiratory cultures have limited sensitivity (35% to 50%) for diagnosing fungal infections until relatively late in the disease process, and radiographic findings lack specificity. Non-culture based tests (NCBT) such as Aspergillus serum galactomannan, serum (1–3)-β-D-glucan, or PCR-based nucleic acid detection have varying sensitivity for diagnosing true infection, but often have sufficiently high negative predictive values to make them useful in conjunction with other methods of clinical assessment to rule out common fungal infections. Therefore, NCBT may facilitate early de-escalation or stopping of empirical therapy in patients without evidence of fungal infection (Maertens 2011). On the other hand, indiscriminate use of NCBT to “screen out” all patients is probably ineffective and expensive. Screening with NCBT must target higher-risk subpopulations, which can be identified from either institutional experience or a validated institutional risk model (score). Several validated risk scores for invasive candidiasis in non-neutropenic ICU [recently reviewed by (Kratzer 2011) and invasive mold disease in hematology patients (Stanzani 2013)] are reported in the literature and appear to be reasonable starting points to help clinicians discriminate lower-risk (ie, incidence of 1% to 2%) versus higher-risk sub-populations (ie, 5% to 20%). Higher-risk subpopulations are more likely to benefit from antifungal prophylaxis or diagnostic screening with NCBT, even in the absence of clinical signs or symptoms (diagnostic-driven approach). Similarly, empirical therapy is initially justified in higher-risk patients with persistent fever, radiographic or other clinical findings (fever-driven approach) but should be reassessed or possibly discontinued if signs or symptoms of infection improve, the patient has with resolving immunosuppression (ie, resolution of neutropenia), and cultures and other NCBTs remain consecutively negative (Stanzani 2013).

The final 2 strategies important for program success are: 1) continual re-assessment of the program’s clinical impact (in terms of prevention and management of IFIs); and 2) analysis of antifungal consumption. Special consideration must be given to how antifungal consumption will be analyzed to

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make sure the reporting variable is not sensitive to the effects of a few outlier patients (ie, prolonged length of stay and antifungal usage; especially in smaller hospitals). Additionally, benchmarking of antifungal consumption based on the defined daily dose (DDD) methodology may overestimate use of fluconazole, itraconazole, and amphotericin B relative to other antifungals (de With 2005). It is also important for antifungal stewardship programs to demonstrate economic value to hospital administrators, as cost-reduction is a common justification for funding or personnel needed to administer the program.

Ultimately, multidisciplinary cooperation is the most important element in the success of an antimicrobial stewardship program and a shared goal to responsibly use antifungal agents in a manner that yields the greatest benefits and lowest risk to patients at risk for invasive fungal diseases.

References Alexander BD, Johnson MD, Pfeiffer CD, et al. Increasing echinocandin resistance in Candida glabrata: clinical failure correlates with presence of FKS mutations and elevated minimum inhibitory concentrations. Clin Infect Dis. 2013;56:1724-1732.

Ananda-Rajah MR, Slavin MA, Thursky KT. The case for antifungal stewardship. Curr Opin Infect Dis. 2012;25:107-115.

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De With K, Steib-Bauert M, Knoth H, et al. Hospital use of systemic antifungal drugs. BMC Clin Pharmacol. 2005;5:1.

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Girmenia C, Micozzi A, Piciocchi A, et al. Invasive fungal diseases during first induction chemotherapy affect complete remission achievement and long-term survival of patients with acute myeloid leukemia. Leuk Res. 2014;38:469-474.

Greene RE, Schlamm HT, Oestmann J-W, et al. Imaging findings in acute invasive pulmonary aspergillosis: clinical significance of the halo sign. Clin Infect Dis. 2007;44:373-379.

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