Real-life comparison of posaconazole versus fluconazole for primary antifungal prophylaxis during remission-induction chemotherapy for acute leukemia.

Background: Patients undergoing remission-induction intensive chemotherapy for acute leukemia are at high risk for life-threatening invasive fungal infections (IFIs). Primary antifungal prophylaxis with posaconazole has been shown to reduce the incidence of IFI compared to fluconazole, but real-life data are limited and the effect on mortality remains unclear. Methods: This retrospective cohort study compared fluconazole and posaconazole as primary prophylaxis in real-life practice over a 10-year period, in a Canadian hospital. Results: A total of 299 episodes were included (fluconazole, n = 98; posaconazole, n = 201), of which 68% were first inductions. The underlying hematologic malignancy was acute myeloid leukemia or myelodysplastic syndrome in 88% of episodes and acute lymphoblastic leukemia in 9%. Overall, 20 cases of IFI occurred (aspergillosis, n = 17; candidiasis, n = 3) and 14 were considered as breakthrough IFI. IFI incidence was significantly lower in the posaconazole group (3.5% versus 13.2%; p = 0.001). Empirical or targeted antifungal therapy was also reduced in the posaconazole cohort. Mortality was similar in both groups. Conclusions: In a real-life setting in Canada, primary posaconazole prophylaxis reduces the incidence of IFI during remission-induction chemotherapy, compared to fluconazole.

Historique: Les patients soumis à une chimiothérapie intensive visant à induire la rémission d'une leucémie aiguë sont très vulnérables à des infections fongiques invasives (IFI) au potentiel mortel. Il est démontré qu'une prophylaxie antifongique primaire au posaconazole réduit l'incidence d'IFI davantage que le fluconazole, mais les données sur le terrain sont limitées et l'effet de ce médicament sur la mortalité demeure nébuleux. Méthodologie: La présente étude de cohorte rétrospective a comparé le fluconazole au posaconazole comme prophylaxie primaire sur une période de dix ans dans un hôpital canadien. Résultats: Au total, 299 épisodes ont été inclus (fluconazole, n = 98; posaconazole, n = 201), dont 68 % étaient des premières occurrences. Dans 88 % des épisodes, la leucémie myéloïde était le cancer hématologique sous-jacent, et dans 9 % des cas, il s'agissait plutôt d'une leucémie aiguë lymphoblastique. Dans l'ensemble, 20 cas d'IFI ont été observés (aspergillose, n = 17; candidose, n = 3) et 14 étaient considérés comme des IFI qui avaient percé malgré une médication. L'incidence d'IFI était beaucoup plus faible dans le groupe prenant du posaconazole (3,5 % par rapport à 13,2 %; p = 0,001). Le traitement antifongique empirique ou ciblé était également limité dans cette cohorte. La mortalité était semblable dans les deux groupes. Conclusions: Sur le terrain au Canada, la prophylaxie primaire au posaconazole réduit l'incidence d'IFI davantage que le fluconazole pendant une chimiothérapie visant à induire une rémission.

Species distribution and antifungal susceptibility of invasive Candida isolates from Canadian hospitals: results of the CANWARD 2011-16 study.

OBJECTIVES: Understanding the epidemiology of invasive Candida infections is essential to patient management decisions and antifungal stewardship practices. This study characterized the species distribution and antifungal susceptibilities of prospectively collected isolates of Candida species causing bloodstream infections (BSIs) in patients admitted to tertiary care hospitals located in 14 cities across 8 of the 10 Canadian provinces between 2011 and 2016. METHODS: Antifungal susceptibility testing was performed by broth microdilution using CLSI methods, breakpoints and epidemiological cut-off values. DNA sequencing of fks loci was performed on all echinocandin-non-susceptible isolates. RESULTS: Candida albicans (49.6%), Candida glabrata (20.8%) and Candida parapsilosis complex (12.0%) were the most common species out of 1882 isolates associated with BSIs. Candida tropicalis (5.2%), Candida krusei (4.3%), Candida dubliniensis (4.1%), Candida lusitaniae (1.4%) and Candida guilliermondii (1.1%) were less frequently isolated. Between 2011 and 2016, the proportion of C. albicans significantly decreased from 60.9% to 42.1% (P < 0.0001) while that of C. glabrata significantly increased from 16.4% to 22.4% (P = 0.023). C. albicans (n = 934), C. glabrata (n = 392) and C. parapsilosis complex (n = 225) exhibited 0.6%, 1.0% and 4.9% resistance to fluconazole and 0.1%, 2.5% and 0% resistance to micafungin, respectively. Mutations in fks hot-spot regions were confirmed in all nine micafungin non-susceptible C. glabrata. CONCLUSIONS: Antifungal resistance in contemporary isolates of Candida causing BSIs in Canada is uncommon. However, the proportion of C. glabrata isolates has increased and echinocandin resistance in this species has emerged. Ongoing surveillance of local hospital epidemiology and appropriate antifungal stewardship practices are necessary to preserve the utility of available antifungal agents.

Risk factors for the development of Clostridium difficile infection in adult allogeneic hematopoietic stem cell transplant recipients: A single-center study in Québec, Canada.

BACKGROUND: Clostridium difficile infection (CDI) is a significant complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Our primary objective was to determine risk factors for the development of CDI during the first year following allo-HSCT. METHODS: A matched case-control study nested in a cohort of allo-HSCT at a single hospital in Montréal, Québec, Canada, was conducted from 2002 through 2011. RESULTS: Sixty-five of 760 patients who underwent allo-HSCT between 2002 and 2011 developed CDI, representing an incidence of 8.6%. We selected 123 controls matched for year of transplant for risk factor analyses. In the multivariable analysis, receipt of trimethoprim-sulfamethoxazole (TMP-SMX) prior to transplantation (adjusted odds ratio [aOR] 0.07, 95% confidence interval [CI] 0.02-0.27), mucositis (aOR 5.90, 95% CI 2.08-16.72), and reactivation of cytomegalovirus (CMV) (aOR 6.17, 95% CI 2.17-17.57) and of other Herpesviridae viruses (aOR 3.04, 95% CI 1.13-8.16) were the variables that remained statistically associated with CDI. High-risk antibiotic use in the late post-transplant period (aOR 7.63, 95% CI 2.14-27.22) was associated with development of late CDI. CONCLUSION: This study revealed reactivation of CMV and other Herpesviridae viruses as novel risk factors for CDI. Administration of TMP-SMX prior to transplantation was independently associated with a decreased risk of CDI. Early and late CDI after HSCT may have distinct risk factors.

High frequency of pathogenic Aspergillus species among nonsporulating moulds from respiratory tract samples.

Nonsporulating moulds (NSM) represent an identification challenge for clinical laboratories. Data on the prevalence of pathogenic species among NSM are lacking. We prospectively investigated consecutive thermotolerant (36°C) clinical NSM isolates from respiratory tract samples. A total of 123 isolates were identified by DNA sequencing and phenotypically characterized. Of those, 13 (11%) were pathogenic species (Aspergillus fumigatus, n = 10; A. flavus, n = 1; A. hiratsukae, n = 1; Schizophyllum commune, n = 1). Presumptive identification of Aspergillus species among NSM can be achieved by simple phenotypic testing.

Phase 3 pharmacokinetics and safety study of a posaconazole tablet formulation in patients at risk for invasive fungal disease.

BACKGROUND: Antifungal prophylaxis with a new oral tablet formulation of posaconazole may be beneficial to patients at high risk for invasive fungal disease. A two-part (Phase 1B/3) study evaluated posaconazole tablet pharmacokinetics (PK) and safety. METHODS: Patients with neutropenia following chemotherapy for haematological malignancy or recipients of allogeneic HSCT receiving prophylaxis or treatment for graft-versus-host disease received 300 mg posaconazole (as tablets) once daily (twice daily on day 1) for up to 28 days without regard to food intake. Weekly trough PK sampling was performed during therapy, and a subset of patients had sampling on days 1 and 8. Cmin-evaluable subjects received ≥6 days of dosing, and were compliant with specified sampling timepoints. Steady-state PK parameters, safety, clinical failure and survival to day 65 were assessed. ClinicalTrials.gov, NCT01777763; EU Clinical Trials Register, EUDRA-CT 2008-006684-36. RESULTS: Two hundred and ten patients received 300 mg posaconazole (as tablets) once daily. Among Cmin-evaluable subjects (n = 186), steady-state mean Cmin was 1720 ng/mL (range = 210-9140). Steady-state Cmin was ≥700 ng/mL in 90% of subjects with 5% (10 of 186) <500 ng/mL and 5% (10 of 186) 500-700 ng/mL. Six (3%) patients had steady-state Cmin ≥3750 ng/mL. One patient (<1%) had an invasive fungal infection. The most common treatment-related adverse events were nausea (11%) and diarrhoea (8%). There was no increase in adverse event frequency with higher posaconazole exposure. CONCLUSIONS: In patients at high risk for invasive fungal disease, 300 mg posaconazole (as tablets) once daily was well tolerated and demonstrated a safety profile similar to that reported for posaconazole oral suspension: most patients (99%) achieved steady-state pCavg exposures >500 ng/mL and only one patient (<1%) had a pCavg <500 ng/mL.

Guidance for practitioners on the use of antiviral drugs to control influenza outbreaks in long-term care facilities in Canada, 2014-2015 season.

The AMMI Canada Guidelines document 'The use of antiviral drugs for influenza: A foundation document for practitioners', published in the Autumn 2013 issue of the Journal, outlines the recommendations for the use of antiviral drugs to treat influenza. This article, which represents the first of two updates to these guidelines published in the current issue of the Journal, aims to inform health care professionals of the increased risk for influenza in long-term care facilities due to a documented mismatch between the components chosen for this season's vaccine and currently circulating influenza strains. Adjusted recommendations for the use of antiviral drugs for influenza in long-term care facilities for this season are provided.

Guidance on the use of antiviral drugs for influenza in acute care facilities in Canada, 2014-2015.

This article represents the second update to the AMMI Canada Guidelines document on the use of antiviral drugs for influenza. The article aims to inform health care professionals of the increased risk for influenza in long-term care facilities due to a documented mismatch between the components chosen for this season's vaccine and currently circulating influenza strains. Adjusted recommendations for the use of antiviral drugs for influenza in the acute care setting for this season are provided.

Incidence of invasive aspergillosis following remission-induction chemotherapy for acute leukemia: a retrospective cohort study in a single Canadian tertiary care centre.

BACKGROUND: The decision to use universal primary antimould prophylaxis to prevent invasive aspergillosis in patients with acute leukemia depends on the incidence of infection at individual centres. We determined our institution's incidence of invasive aspergillosis among patients who received remission-induction chemotherapy for acute leukemia to evaluate the potential benefits of primary antimould prophylaxis. METHODS: We conducted this retrospective cohort study at a Canadian tertiary care centre. From the central pharmacy registries, we retrieved records for all adult patients for whom remission-induction chemotherapy for acute leukemia was prescribed between 2008 and 2010. We retrieved clinical, microbiologic, pathologic and radiologic data from the patients' medical charts. The primary outcome was a diagnosis of probable or proven invasive aspergillosis up to 180 days after resolution of aplasia. RESULTS: We retrieved records for 123 patients with acute leukemia. Twenty-two of these patients did not receive the prescribed chemotherapy and were excluded from the analysis. Of the 101 patients included, 77 (76.2%) had acute myeloid leukemia. Overall, 136 courses of chemotherapy were administered, with more than 1 course administered to 26 (25.7%) of the 101 patients. In 9 of the patients (8.9%; 95% confidence interval 4.2%-16.2%), invasive aspergillosis was diagnosed (3 proven and 6 probable cases) a median of 19 (range 11-34) days after initiation of chemotherapy. In 7 (78%) of these 9 patients, invasive aspergillosis occurred during the first course of chemotherapy. Three patients died within the first year after diagnosis of invasive aspergillosis. INTERPRETATION: We found a high incidence (8.9%) of invasive aspergillosis at our centre. This finding triggered the introduction of targeted antimould prophylaxis for patients with acute leukemia who were undergoing remission-induction chemotherapy.

Phase 1b study of new posaconazole tablet for prevention of invasive fungal infections in high-risk patients with neutropenia.

Posaconazole tablets, a new oral formulation of posaconazole, can be effective when given as antifungal prophylaxis to neutropenic patients at high risk for invasive fungal infection (e.g., those with acute myelogenous leukemia or myelodysplastic syndrome). Such effectiveness might be specifically important to patients with poor oral intake because of nausea, vomiting, or chemotherapy-associated mucositis. This was a prospective, global study in high-risk patients to characterize the pharmacokinetics and safety profile of posaconazole tablets and to identify the dose of posaconazole tablets that would provide exposure within a predefined range of exposures (steady-state average concentration [area under the concentration-time curve/24 h] of ≥500 ng/ml and ≤2,500 ng/ml in >90% of patients). The study evaluated two sequential dosing cohorts: 200 mg posaconazole once daily (n = 20) and 300 mg posaconazole once daily (n = 34) (both cohorts had a twice-daily loading dose on day 1) taken without regard to food intake during the neutropenic period for ≤28 days. The exposure target was reached (day 8) in 15 of 19 (79%) pharmacokinetic-evaluable patients taking 200 mg posaconazole once daily and in 31 of 32 (97%) patients taking 300 mg posaconazole once daily; 300 mg posaconazole once daily achieved the desired exposure target. Posaconazole tablets were generally well tolerated in high-risk neutropenic patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT01777763.).

The Prospective Antifungal Therapy Alliance(®) registry: A two-centre Canadian experience.

BACKGROUND: The Prospective Antifungal Therapy Alliance(®) registry is a prospective surveillance study that collected data on the diagnosis, management and outcomes of invasive fungal infections (IFIs) from 25 centres in North America from 2004 to 2008. OBJECTIVE: To evaluate surveillance data on IFIs obtained from study centres located in Canada. METHODS: Patients with proven or probable IFIs at two Canadian medical centres were enrolled in the registry. Information regarding patient demographics, fungal species, infection sites, diagnosis techniques, therapy and survival were analyzed. RESULTS: A total of 347 patients from Canada with documented IFIs were enrolled in the Prospective Antifungal Therapy Alliance registry. Infections occurred most commonly in general medicine (71.8%), nontransplant surgery (32.6%) and patients with hematological malignancies (21.0%). There were 287 proven IFIs, including 248 Candida infections. Forty-six patients had invasive aspergillosis (IA); all of these were probable infections. Most cases of invasive candidiasis were confirmed using blood culture (90.5%), while IA was most frequently diagnosed using computed tomography scan (82.6%) and serological methods (82.6%). Fluconazole was the most common therapy used for Candida infections, followed by the echinocandins. Voriconazole therapy was most commonly prescribed for IA. CONCLUSIONS: The present study demonstrated that general medicine, surgery and hematological malignancy patients in Canada are susceptible to developing IFIs. In contrast to the United States, Candida albicans remains responsible for most IFIs in these Canadian centres. Surrogate serum markers are commonly being used for the diagnosis of IA, while therapy for both IFIs has shifted to broader-spectrum azoles and echinocandins.

HISTORIQUE: Le registre PATH de la Prospective Antifungal Therapy Alliance est une étude de surveillance prospective qui a permis de colliger des données sur le diagnostic, la prise en charge et les issues des infections fongiques invasives (IFI) provenant de 25 centres d'Amérique du Nord entre 2004 et 2008. OBJECTIF: Évaluer les données de surveillance sur les IFI provenant de centres d'études situés au Canada. MÉTHODOLOGIE: Les patients ayant une IFI démontrée ou probable provenant de deux centres médicaux canadiens ont été inscrits au registre. Les chercheurs ont analysé l'information portant sur la démographie des patients, les espèces fongiques, les foyers d'infection, les techniques diagnostiques, la thérapie et la survie. RÉSULTATS: Au total, 347 patients du Canada ayant une IFI vérifiée ont été inscrits au registre PATH. Les infections se produisaient surtout en médecine générale (71,8 %), en chirurgie pour autre chose que des transplantations (32,6 %) et chez les patients ayant une tumeur hématologique maligne (21,0 %). Ainsi, 287 IFI ont été démontrées, y compris 248 infections à Candida. Quarante-six patients avaient une aspergillose invasive (AI), qui étaient toutes des infections probables. La plupart des candidoses invasives ont été confirmées par des prélèvements sanguins (90,5 %), tandis que les AI étaient surtout diagnostiquées par tomodensitométrie (82,6 %) et méthodes sérologiques (82,6 %). Le fluconazole était le traitement le plus utilisé pour traiter les infections à Candida, suivi des échinocandines. Quant au traitement au voriconazole, c'était le plus prescrit pour l'AI. CONCLUSIONS: La présente étude a démontré qu'au Canada, les patients en médecine générale, en chirurgie et ayant une tumeur hématologique maligne sont susceptibles de contracter une IFI. Contrairement aux États-Unis, le Candida albicans demeure responsable de la plupart des IFI dans ces centres canadiens. Des marqueurs sériques de remplacement sont souvent utilisés pour diagnostiquer l'AI, tandis que le traitement des deux IFI est désormais assuré par des aux azoles et des échinocandines à large spectre.

Therapeutic drug monitoring for triazoles: A needs assessment review and recommendations from a Canadian perspective.

Invasive fungal infections cause significant morbidity and mortality in patients with concomitant underlying immunosuppressive diseases. The recent addition of new triazoles to the antifungal armamentarium has allowed for extended-spectrum activity and flexibility of administration. Over the years, clinical use has raised concerns about the degree of drug exposure following standard approved drug dosing, questioning the need for therapeutic drug monitoring (TDM). Accordingly, the present guidelines focus on TDM of triazole antifungal agents. A review of the rationale for triazole TDM, the targeted patient populations and available laboratory methods, as well as practical recommendations based on current evidence from an extended literature review are provided in the present document.

Les infections fongiques invasives sont responsables d'une morbidité et d'une mortalité importantes chez les patients atteints d'une maladie immunodépressive. L'ajout des nouveaux triazoles aux traitements antifongiques a élargi le spectre d'activité et la flexibilité d'administration. Au fil des ans, leur utilisation clinique a suscité des inquiétudes quant au degré d'exposition au médicament selon une posologie approuvée standard, ce qui soulève la nécessité de la pharmacovigilance thérapeutique (PVT). Les présentes lignes directrices portent donc sur la PVT des antifongiques triazolés. Dans le présent document sont exposées une analyse de la raison d'être de la PVT des triazoles, les populations de patients ciblées et les méthodes de laboratoire offertes, de même que des recommandations pratiques fondées sur des données probantes à jour tirées d'une analyse bibliographique approfondie.

Why Candida sepsis should matter to ICU physicians.

The incidence of candidemia and invasive Candida infections has increased substantially over the last 2 decades. These infections are associated with risk factors that characterize intensive care unit patients. Candidemia and invasive Candida are highly morbid and associated with significantly increased mortality. Outcomes in the intensive care setting depend on physician awareness and rapid intervention. The epidemiology of the disease, its diagnostic challenges, and management strategies, including prophylactic, preemptive, and definitive therapeutic approaches, are presented herein.

Clostridium difficile infection after adult autologous stem cell transplantation: a multicenter study of epidemiology and risk factors.

We sought to describe the epidemiology of Clostridium difficile infection (CDI) among adult recipients of autologous hematopoietic stem cell transplantation (auto-HSCT) within the first year after HSCT in centers with variable epidemiology of hypertoxigenic strains. A multicenter, retrospective nested case-control study was conducted among 873 auto-HSCT recipients at Johns Hopkins Hospital (JHH) and Hôpital Maisonneuve-Rosemont (HMR) between January 2003 and December 2008. Despite center differences in the prevalence of NAP-1 strains during the study period (21% to 43% at JHH versus 80% to 84% in HMR), the 1-year incidence of CDI was similar in the 2 hospitals (6.2% at JHH versus 5.7% at HMR). The median time to infection was 11 days (interquartile range, 1 to 27 days). In case-control analyses, grade ≥2 mucositis (odds ratio [OR], 3.00; P = .02) and receipt of a fourth-generation cephalosporin (OR, 2.76; P = .04) were identified as predictors for CDI. Mucositis was the strongest predictor of risk for CDI in multivariate analysis (adjusted OR, 2.77; P = .03). CDI is a common and early complication of auto-HSCT. Treatment-related gastrointestinal mucosal damage, along with the potentially modifiable risk of antimicrobial exposure, influence the risk for CDI early after auto-HSCT.

Treatment of invasive candidiasis in neutropenic patients: systematic review of randomized controlled treatment trials.

Candidemia and invasive candidiasis (CIC) is associated with considerable morbidity and mortality, with a paucity of controlled data in neutropenic patients. A systematic review was conducted of available data for the treatment of CIC during neutropenia. A structured OVID search of multiple databases was performed. Data from randomized controlled trials of CIC and of empirical antifungal therapy in febrile neutropenic patients was included. A total of 17 trials randomizing 342 neutropenic patients were included. Eight of the studies compared amphotericin B (AmB) to other non-polyene antifungal agents. Pooling of results favored use of comparator compounds (odds ratio [OR] 0.73; 95% confidence interval [CI] 0.42-1.29). To strengthen our analysis, a pre-planned sensitivity analysis was also conducted. Overall, there was a non-significant benefit in favor of non-polyene compounds. Across studies, echinocandins provided the benefit of favorable outcomes with fewest side effects and toxicity.

A case of Japanese encephalitis virus infection acquired during a trip in Thailand.

A case of Japanese encephalitis virus (JEV) infection is reported in a young traveler returning from Thailand. Clinical suspicion of JEV in travelers returning from endemic areas with neurologic symptoms is warranted. Confirmation of the diagnosis is complex and requires specialized laboratory services. Individualized advice on the costs and benefits of vaccination is recommended.

Ten-year experience with fungal peritonitis in peritoneal dialysis patients: antifungal susceptibility patterns in a North-American center.

OBJECTIVE: To describe the clinical and microbiological features associated with fungal peritonitis in peritoneal dialysis (PD) patients at Hôpital Maisonneuve-Rosemont, from August 1996 to July 2006. METHODS: Cases were retrieved from the microbiology laboratory culture registry. Antifungal susceptibility was determined by the Clinical and Laboratory Standards Institute M27A3 method. RESULTS: Among 288 PD patients (total follow-up of 7258 patient-months), nine were found with fungal peritonitis. Candida spp were identified in all of them, with a majority of non-albicans Candida species. Resistance to fluconazole, itraconazole, or voriconazole was as frequent as potential resistance to amphotericin B. No isolate was resistant to caspofungin and one was resistant to micafungin. Prior bacterial peritonitis was frequent (67%). All patients had their PD catheter removed and all of them survived. CONCLUSIONS: In our institution, fungal peritonitis in PD patients is rare. All cases were caused by Candida species. Variable susceptibility patterns were observed, which may influence the initial empirical antifungal therapy and underscore the importance of individual speciation and susceptibility testing of invasive Candida isolates.

In vitro activity of ceftobiprole against frequently encountered aerobic and facultative Gram-positive and Gram-negative bacterial pathogens: results of the CANWARD 2007-2009 study.

The in vitro activity of ceftobiprole was evaluated against 15 011 clinical isolates obtained from patients in Canadian hospitals between 2007 and 2009. All Staphylococcus aureus were susceptible to ceftobiprole (MIC(90)'s for methicillin-susceptible Staphylococcus aureus and methicillin-resistant Staphylococcus aureus of ≤ 1 µg/mL and 2 µg/mL, respectively). Ceftobiprole was active against penicillin-susceptible Streptococcus pneumoniae (MIC(90), ≤ 0.06 µg/mL), penicillin-resistant Streptococcus pneumoniae (MIC(90), 0.5 µg/mL), Streptococcus pyogenes (MIC(90), ≤ 0.06 µg/mL), Staphylococcus epidermidis (MIC(90), ≤ 1 µg/mL), and Enterococcus faecalis (MIC(90), ≤ 1 µg/mL). Over 90% of Escherichia coli, Klebsiella pneumoniae, Enterobacter aerogenes, Citrobacter freundii, Proteus mirabilis, and Serratia marcescens isolates were inhibited by a ceftobiprole concentration of ≤ 1 µg/mL. Ceftobiprole was not active against extended-spectrum ß-lactamase-producing Escherichia coli and K. pneumoniae. The in vitro activity of ceftobiprole versus Pseudomonas aeruginosa was similar to that of cefepime (MIC(90), 16 µg/mL). The broad spectrum of activity by ceftobiprole would support further study of this agent in the treatment of hospital-acquired infections.