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ObjectivesUnderstanding 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.MethodsAntifungal 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.ResultsCandida 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 ConclusionsAntifungal 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.

Influenza vaccine is recommended annually to reduce the influenza-associated disease burden, particularly among those at high risk of serious influenza complications ( 1 ). However, a potential for low vaccine effectiveness (VE) has been identified for the 2017–2018 influenza season. To address that concern, the following antiviral drug recommendations have been revised (see Table 1 , changes in bold) from the AMMI Canada Foundation Document ( 2 ).

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.

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.To evaluate surveillance data on IFIs obtained from study centres located in Canada.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.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.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.Le registre PATH de laÉvaluer les données de surveillance sur les IFI provenant de centres d’études situés au Canada.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.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 àLa 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

Therapeutic drug monitoring (TDM) is necessary for certain drugs to ensure that the levels are sufficient to be effective, but not so high as to cause adverse effects. This review summarizes the literature regarding TDM for newer-generation extended-spectrum triazoles, including when TDM may be necessary for each drug and why, and laboratory techniques used for the measurement of levels of these drugs. The document includes recommendations for the use of TDM for each triazole that is discussed., 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.

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 Montreal, Quebec, 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.

Although the use of nonmyeloablative (NMA) hematopoietic stem cell transplantation (HSCT) regimens has expanded in the past decade, little data exist to support antiviral prophylaxis to prevent herpes zoster (HZ) in recipients who are seropositive for varicella-zoster virus in this population. The present study examined the clinical features, incidence, and risk factors for HZ in a homogeneous cohort of NMA allogeneic HSCT recipients. We conducted a retrospective cohort study assessing all patients who underwent sibling NMA HSCT at Maisonneuve-Rosemont Hospital (Montreal) between July 2000 and December 2008. All patients received the same conditioning regimen, immunoprophylaxis, and graft-versus-host disease therapy. The diagnosis of HZ was defined clinically. Factors associated with HZ were identified using a Cox proportional hazards model. A total of 179 patients were followed for a median of 33 months (interquartile range, 21-59). HZ developed in 66 patients (37%) at a median of 8.3 months post-HSCT; the incidence rate was 175 cases/1000 person-years. The estimated cumulative HZ incidence was 27% at 1 year, 36% at 2 years, and 44% at 3 years. Thoracic dermatomes were most frequently involved (30%); dissemination occurred in 5 patients. No deaths resulted from HZ, but 23% of patients developed postherpetic neuralgia. In multivariate analysis, reactivation of cytomegalovirus and herpes simplex virus was associated with a reduced likelihood of HZ (hazard ratio, 0.54 and 0.33, respectively). Antiviral prophylaxis or treatment for cytomegalovirus and herpes simplex virus reactivations were protective against HZ. The incidence of HZ in our cohort of NMA HSCT recipients is similar to the incidence reported in HSCT recipients who received a myeloablative conditioning regimen. Given the observed high risk, we conclude that recommendations for antiviral prophylaxis should apply, at least for the first year, to the NMA HSCT population as well.

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 β-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.

We conducted a single-center retrospective cohort study to determine the performance characteristics of the galactomannan (GM) assay in bronchoalveolar lavage (BAL) in patients with hematologic malignancies. Patients were classified as proven, probable, possible, or no invasive pulmonary aspergillosis (IPA), according to international guidelines. A total of 173 BAL samples from 145 patients were included. There were 5 proven, 7 probable, and 35 possible cases of IPA. Using a GM index cutoff of ≥ 0.5, the sensitivity, specificity, and positive and negative predictive values (PPV and NPV, respectively) of the BAL GM assay were 100%, 78%, 26%, and 100%, respectively. Using a GM index cutoff of ≥ 2.0, the sensitivity and NPV remained 100%, but specificity and PPV increased to 93% and 50%, respectively. The BAL GM assay is a highly sensitive screening test for IPA in patients with hematologic malignancies. Increasing the cutoff value to 2.0 would improve the performance of this assay.

To evaluate caspofungin in high-risk invasive aspergillosis (IA) patient, a retrospective review of patient characteristics, antifungal therapies and clinical outcomes on hospitalised patients at sites in Russia, Canada, Germany, and Thailand was performed. Fifty-five patients were included, six with proven and 49 with probable aspergillosis; 76.4% had haematological diseases, 80% were on immunosuppressive drugs, 32.7% were neutropenic at caspofungin initiation. Median duration of prior antifungal therapy was 9 days (range 1-232). Reasons for initiating caspofungin included: disease refractory to first-line antifungal (49.1%) and toxicities with prior antifungals (18.2%). Median caspofungin therapy duration was 14 days (range 2-62), with a median of 13 days (range 1-62) as monotherapy. Favourable responses were observed in 45.5% of the patients, complete responses in 40% and partial responses in 5.5%; 74.5% survived 7 days after completion of caspofungin therapy with 69.1% having been successfully discharged from the hospital. Few patients (14.6%) on caspofungin switched because of suspected resistance, lack of response or adverse events. There were no increases in hospital stay as a result of adverse events or drug-drug interactions related to caspofungin; 7.3% of patients had a mean value of 13 (± 14.11) days of increased stay attributable to treatment failure. Caspofungin was well-tolerated. It exhibited effectiveness and high survival in treating severe IA patients.

Azoles are the mainstay of oral therapy for aspergillosis. Azole resistance in Aspergillus has been reported infrequently. The first resistant isolate was detected in 1999 in Manchester, UK. In a clinical collection of 519 A. fumigatus isolates, the frequency of itraconazole resistance was 5%, a significant increase since 2004 (p

OBJECTIVE: To describe the clinical and microbiological features associated withCandidabloodstream infections observed at Hôpital Maisonneuve-Rosemont (Montreal, Quebec) between August 1996 and July 2006.METHODS: Episodes were retrieved from the microbiology laboratory. Different patient episodes and different isolate episodes in the same patient were selected. Antifungal susceptibility was determined by the Clinical and Laboratory Standards Institute’s (USA) M27A2 method.RESULTS: A total of 190 different episodes of candidemia in 185 patients were identified. Eleven (6%) episodes occurred in outpatients.Candida albicanswas identified in the majority of episodes (57%). Its frequency remained stable over the years. The proportion ofCandida kruseicandidemia episodes increased between 2003 and 2006, but this was not statistically significant. A central venous indwelling catheter or a peripherally inserted central catheter line was present in the majority of patients (167 [88%]). Of the indwelling catheters removed at the time of diagnosis, 39% were positive forCandidaspecies on culture. Overall, voriconazole was the most active agent (the minimum inhibitory concentration required to inhibit the growth of 90% of organisms was 0.5 mg/L). Resistance to fluconazole was observed in 26 (14%) isolates (C albicans,4%; versus non-albicans Candidaspecies, 27%; PCONCLUSIONS: At Hôpital Maisonneuve-Rosemont, the frequency and species distribution of blood isolates ofCandidaremained stable over the past decade. In vitro resistance ofC albicansto fluconazole and itraconazole remained minimal; resistance of non-albicans Candidaspecies to fluconazole did not increase significantly. The new antifungal agents all had high in vitro activity against the bloodstreamCandidaisolates.

BACKGROUND: Between May 2003 and April 2005, a population-based surveillance ofCandidabloodstream infections was conducted in Quebec. A total of 453 episodes of candidemia (464 yeast isolates) from 54 participating hospitals were studied.RESULTS: The annual incidence rate was three per 100,000 population. Global hospital mortality was 38%. The most common predisposing factors were the presence of an intravascular catheter (80%), use of antibacterial therapy (67%), stay in an intensive care unit (49%), use of parenteral nutrition (32%) and intra-abdominal surgery (31%). Fluconazole alone or in association with other antifungals was used for treatment in over 80% of cases.Candida albicanscomprised 62% of isolates, followed byCandida glabrata(17%),Candida parapsilosis(9%),Candida tropicalis(5%),Candida lusitaniae(3%) andCandida krusei(3%). Of the 288C albicansisolates, seven (2%) were resistant to flucytosine, one to fluconazole and none to itraconazole or voriconazole. Of the 75 non-C albicansspecies isolates with reduced susceptibility to fluconazole (minimum inhibitory concentration [MIC] 16 μg/mL or greater), none were susceptible to itraconazole (MIC 0.12 mg/L or lower), whereas 71 (95%) were susceptible to voriconazole (MIC 1 μg/mL or lower). However, only five of 12 (42%) fluconazole-resistant isolates were susceptible to voriconazole. Posaconazole, ravuconazole and caspofungin displayed a broad spectrum of activity against these isolates, with MICs of 1 mg/L or lower in 56%, 92% and 100% of isolates, respectively. Overall, a correlation (r2>0.87) was observed among increasing fluconazole MICs and the geometric mean MICs of itraconazole, voriconazole, posaconazole and ravuconazole.CONCLUSIONS: These surveillance results when compared with those of the 1993 to 1995 survey confirm little variation in the distribution of species causing invasiveCandidainfection over a 10-year period in Quebec, as well as the continuous excellent overall in vitro activity of fluconazole.

Invasive aspergillosis (IA) remains a major complication following allogeneic hematopoietic stem cell transplant (HSCT). In contrast to conventional HSCT, few investigators have examined risk factors of IA associated with nonmyeloablative (NMA) regimens characterized by outpatient administration, immunosuppression rather than cytoreduction, and short duration of neutropenia posttransplant. We report our results on a cohort of 125 patients treated homogenously who received a 6/6 matched sibling NMA HSCT designed to be performed on an outpatient basis. Conditioning regimen included fludarabine (30 mg/m 2 × 5 days) and cyclophosphamide (300 mg/m 2 × 5 days) followed by reinfusion of a minimum of 4 × 10 6 CD34 + cells/kg. Acute graft-versus-host disease (aGVHD) prophylaxis consisted of tacrolimus and mycophenolate mofetil (MMF). Overall, 13 patients developed IA (5 proved, 6 probable, 2 possible) 44-791 days (median 229) after NMA HSCT, with a risk of 7% at 1, 11% at 2, and 15% at 3 years. Patients who suffered from IA had poorer overall survival (crude hazard ratio 2.3; 95% confidence interval [CI] 1.0-5.4; P = .045). Intestinal aGVHD or chronic GVHD (cGVHD) was significantly associated with IA at 1 (27% versus 3%, P = .003), 2 (27% versus 8%, P = .01), and 3 years (37% versus 10%, P = .005). The use of daclizumab was also significantly associated with IA at 3 years (47% versus 12%, P = .02). Age, sex, diagnosis, previous autologous transplant, duration of neutropenia, occurrence of cytomegalovirus viremia, duration of steroids or MMF intake, aGVHD, cGVHD, and cumulative number of days spent in hospital were not associated with IA. After multivariate analysis, intestinal GVHD remained the only statistically significant risk factor for IA at 1 ( P = .003), 2 ( P = .01), and 3 years ( P = .005). We conclude that in NMA HSCT, the risk of IA increases over time and is significantly associated with intestinal GVHD. Because there is currently no surrogate in vitro markers of immunocompetence following NMA HSCT, this clinical finding is of particular importance to identify a population at higher risk who should be targeted for antimold prophylaxis.

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. C(min)-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 C(min)-evaluable subjects (n = 186), steady-state mean C(min) was 1720 ng/mL (range = 210–9140). Steady-state C(min) was ≥700 ng/mL in 90% of subjects with 5% (10 of 186) 500 ng/mL and only one patient (

Background Voriconazole (VOR) levels are highly variable, with potential implications to both efficacy and safety. We hypothesized that VOR therapeutic drug monitoring (TDM) will decrease the incidence of treatment failures and adverse events (AEs). Methods We initiated a prospective, randomized, non-blinded multicenter study to compare clinical outcomes in adult patients randomized to standard dosing (clinician-driven) vs. TDM (doses adjusted based on levels). VOR trough levels were obtained on day 5, 14, 28, and 42 (or at completion of drug; ± 3 days). Real-time dose adjustments were made to maintain a range between 1–5 μg/mL on the TDM-arm, while levels were assessed retrospectively in the standard-arm. Patient questionnaires were administered to assess subjective AEs. Results The study was discontinued prematurely, after 29 patients were enrolled. Seventeen (58.6%) patients experienced 38 AEs: visual changes (22/38, 57.9%), neurological symptoms (13/38, 34.2%), and liver abnormalities (3/38, 7.9%). VOR was discontinued in 7 (25%) patients because of an AE (4 standard-arm, 3 TDM-arm). VOR levels were frequently out of range in the standard-arm (8 tests >5 μg/mL; 9 tests

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.

Received 6 September 2006; accepted 6 September 2006;electronically published 13 September 2006.Author affiliations are listed at the end of the text.Reprints or correspondence: Dr. Elias J. Anaissie, MyelomaInstitute for Research and Therapy, University of Arkansasfor Medical Sciences, 4301 W. Markham, Slot 816, LittleRock, AR 72205 (anaissieeliasj@uams.edu).

Received 5 October 2005; returned 15 December 2005; revised 19 December 2005; accepted 17 January 2006 Objectives: To illustrate the progressive loss of cross-echinocandin activity on Candida albicans isolates with strong clonal homology from a patient with advanced HIV infection and chronic oesophagitis progressively resistant to uninterrupted micafungin treatment. Methods: Antifungal susceptibility profiles for different antifungal agents were determined against serial C. albicans isolates retrieved before and during therapy. Multilocus sequencing typing (MLST) was performed on each of the isolates. FKS1 mutations conferring reduced susceptibility to echinocandin drugs were determined by DNA sequence analysis. Results: Four C. albicans isolates showing identical allelic homology were retrieved from the patient at the initiation and during therapy with micafungin. The progressive lack of clinical response to micafungin therapy was associated with increased MICs of all three echinocandin drugs (caspofungin, micafungin and anidulafungin) in association with the acquisition of mutations in the FKS1 gene. Conclusions: This report documents for the first time a progressive loss of activity of all three echinocandin drugs against clonally related C. albicans isolates following long-term clinical exposure to this new class of antifungal agents.

Two clinical Candida albicans isolates that exhibited high-level resistance to azoles and modest decreases in susceptibility to amphotericin B were cultured from unrelated patients. Both isolates harbored homozygous nonsense mutations in ERG3 , which encodes an enzyme, sterol Δ 5,6 -desaturase, involved in ergosterol synthesis. Extraction and analysis of the sterols from both isolates confirmed the absence of sterol Δ 5,6 -desaturase activity. Although the loss of sterol Δ 5,6 -desaturase activity is known to confer resistance to azoles, this mechanism of resistance has rarely been seen in clinical isolates, suggesting that such mutants are at a competitive disadvantage. To test this hypothesis, the virulence of the erg3 mutants was assayed by using a mouse systemic infection model. The mutants were significantly less virulent than the wild-type comparator strains. However, the kidney fungal burdens in mice infected with the erg3 mutants were similar to those in mice infected with the wild-type strains. Similar results were obtained by using a laboratory-generated homozygous erg3 deletion mutant (D. Sanglard et al., Antimicrob. Agents Chemother. 47:2404-2412, 2003). Reintroduction of a wild-type ERG3 allele into the homozygous deletion mutant restored virulence, ergosterol synthesis, and susceptibility to azoles, confirming that these phenotypic changes were solely due to the inactivation of Erg3p.

Background Reported sensitivity of the galactomannan enzyme immunoassay as an early diagnostic test for invasive aspergillosis (IA) has been widely variable, ranging from 29% to 100% in earlier clinical studies. Methods Studies performed to date have analyzed performance using per-patient calculations, limiting their ability to measure the impact of clinical variables that change over time, such as receipt of preventive antifungal therapy. In our study, performance of the test was calculated in per-patient and per-test analyses in a large cohort of patients at high risk for IA from 2 North American centers. A total of 272 serum samples obtained from 46 patients with IA and 3005 serum samples obtained from 269 control patients were analyzed using multiple index cutoff values to define positivity. Results Per-patient calculations yielded sensitivities of 43% and 70% using index cutoff values of 1.5 and 0.5, respectively; specificity decreased from 93% with use of the 1.5 index cutoff to 70% with use of the 0.5 index cutoff. Per-test calculations yielded sensitivities of 31% and 59% and specificities of 99% and 92% using index cutoff values of 1.5 and 0.5, respectively. Receipt of mold-active antifungal drugs on the day of testing decreased sensitivity; samples obtained from patients not receiving prophylactic or empirical antifungal drugs yielded a sensitivity of 89% and a specificity of 92% (with use of an index cutoff value of 0.5). Conclusions These findings have direct implications for preventive strategies, because the diagnostic utility of the antigen assay is compromised during receipt of prophylactic or empirical antifungal therapies.

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.

Summary Objective To describe the clinical and microbiological features associated with fungal peritonitis in peritoneal dialysis (PD) patients at Hopital 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.

We report a randomized, double-blind, multicenter trial in which amphotericin B colloidal dispersion (ABCD [Amphotec]; 6 mg/kg/day) was compared with amphotericin B (AmB; 1.0-1.5 mg/kg/day) for the treatment of invasive aspergillosis in 174 patients. For evaluable patients in the ABCD and AmB treatment groups, respective rates of therapeutic response (52% vs. 51%; P=1.0), mortality (36% vs. 45%; P=.4), and death due to fungal infection (32% vs. 26%; P=.7) were similar. Renal toxicity was lower (25% vs. 49%; P=.002) and the median time to onset of nephrotoxicity was longer (301 vs. 22 days; P

BACKGROUND The overall clinical efficacy of the azoles antifungal agents and low-dose intravenous amphotericin B for antifungal chemoprophylaxis in patients with malignant disease who have severe neutropenia remains unclear. METHODS Randomized-controlled trials of azoles (fluconazole, itraconazole, ketoconazole, and miconazole) or intravenous amphotericin B formulations compared with placebo/no treatment or polyene-based controls in severely neutropenic chemotherapy recipients were evaluated using meta-analytical techniques. RESULTS Thirty-eight trials that included 7014 patients (study agents, 3515 patients; control patients, 3499 patients) were analyzed. Overall, there were reductions in the use of parenteral antifungal therapy (prophylaxis success: odds ratio [OR], 0.57; 95% confidence interval [95% CI], 0.48–0.68; relative risk reduction [RRR], 19%; number requiring treatment for this outcome [NNT], 10 patients), superficial fungal infection (OR, 0.29; 95% CI, 0.20–0.43; RRR, 61%; NNT, 12 patients), invasive fungal infection (OR, 0.44; 95% CI, 0.35–0.55; RRR, 56%; NNT, 22 patients), and fungal infection-related mortality (OR, 0.58; 95% CI, 0.41–0.82; RRR, 47%; NNT, 52 patients). Invasive aspergillosis was unaffected (OR, 1.03; 95% CI, 0.62–1.44). Although overall mortality was not reduced (OR, 0.87; 95% CI, 0.74–1.03), subgroup analyses showed reduced mortality in studies of patients who had prolonged neutropenia (OR, 0.72; 95% CI, 0.55–0.95) or who underwent hematopoietic stem cell transplantation (HSCT) (OR, 0.77; 95% CI, 0.59–0.99). The multivariate metaregression analyses identified HSCT, prolonged neutropenia, acute leukemia with prolonged neutropenia, and higher azole dose as predictors of treatment effect. CONCLUSIONS Antifungal prophylaxis reduced morbidity, as evidenced by reductions in the use of parenteral antifungal therapy, superficial fungal infection, and invasive fungal infection, as well as reducing fungal infection-related mortality. These effects were most pronounced in patients with malignant disease who had prolonged neutropenia and HSCT recipients. Cancer 2002;94:3230–46. © 2002 American Cancer Society. DOI 10.1002/cncr.10610

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.)

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 aspergillo sis 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.

Domestic water supply, and particularly electric hot water systems, have been associated with Legionella colonization, and potential clinical implications have been suggested. In an effort to establish a link between sporadic legionellosis and hot water system colonization, patients hospitalized with documented sporadic community-acquired legionellosis (CAL) at Maisonneuve-Rosemont hospital in Monteral, Canada, were prospectively investigated. Only three culture-confirmed cases of CAL were established during the 30-month prospective epidemiological surveillance study. An epidemiological link between those patients' pneumonia and their contaminated home hot water tank was established in only one patient. The first water samples from this patient's home were obtained 45 days after the patient's admission to the hospital. Additional water samples from the hot water tank taken 14 weeks after the patient's admission showed a persistence in the system of the same isolate, underlying the long-term sustained colonization of contaminated hot water systems. Debilitation by chronic alcoholism and smoking, as well as recent plumbing repair and frequent exposures to aerosols generated from the shower head, likely played predominant physiopathological roles in the patient's acquisition of Legionnaires' disease. A study by the authors focused on severe CAL that required hospitalization and found a very low incidence linked to contaminated hot water tanks. Individual risk factors (i.e., smoking, age, chronic lung diseases) and immunoincompetence rather than environmental factors likely represent the major contributing factors in the acquisition of severe sporadic Legionnaires' disease.

Over the course of a 20-month period, in a hospital respiratory ward in which ciprofloxacin was often used as empirical antimicrobial therapy for lower respiratory tract infections (LRTIs), 16 patients with chronic bronchitis developed nosocomial LRTIs caused by penicillin- and ciprofloxacin-resistant Streptococcus pneumoniae (serotype 23 F). The minimum inhibitory concentration (MIC) of ciprofloxacin for all isolates from the first 9 patients was 4 microg/mL, in association with a parC mutation. Isolates from the subsequent 7 patients all had a ciprofloxacin MIC of 16 microg/mL, in association with an additional mutation in gyrA. The MICs for this isolate were 8 microg/mL of levofloxacin (resistant), 2 microg/mL of moxifloxacin and gatifloxacin (intermediately resistant), and 0.12 microg/mL of gemifloxacin. This outbreak demonstrates the ability of S. pneumoniae to acquire multiple mutations that result in increasing levels of resistance to the fluoroquinolones and to be transmitted from person to person.

New broth-based detection systems have higher recovery rates of mycobacteria from clinical specimens than traditional cultures on solid media. The clinical significance of this higher sensitivity rate is largely unknown. We prospectively evaluated the performances of two liquid media detection systems (the MB/BacT system and the BACTEC 460 TB system) and an egg-based Lowenstein-Gruft solid medium (LG) on the recovery rates of mycobacteria from 849 clinical specimens. Mycobacteria (other then M. gordonae) were detected in 51 (6.0%) specimens. In 12/51 (23%) specimens, mycobacteria (five mycobacterium tuberculosis (MtB) and seven non-M tuberculosis complex (MOTT) were recovered only from the broth-based systems. Review of the patients' clinical charts revealed that failure of LG to recover Mtb were due to nonmycobacterial overgrowth and antibiotic treatment. The recovered MOTT were all clinically nonsignificant. Higher sensitivity of broth-based mycobacteria detection systems is largely due to their capability to recover mycobacteria from treated tuberculous patients or from partially decontaminated specimens. The high recovery rates of nonclinically significant MOTT could potentially increase inappropriate use of antibiotics.

A randomized, double-blind trial comparing oral fluconazole (400 mg daily) with placebo as prophylaxis for adult patients receiving intensive cytotoxic therapy for acute leukemia or autologous bone marrow transplantation was conducted in 14 Canadian university-affiliated hospitals. Although fluconazole prophylaxis did not obviate the need for parenteral antifungal therapy compared with placebo (81 [57%] of 141 vs. 67 [50%] of 133, respectively), its use resulted in fewer superficial fungal infections (10 [7%] of 141 vs. 23 [18%] of 131, respectively; P = .02) and fewer definite and probable invasive fungal infections (9 vs. 32, respectively; P = .0001). Fluconazole recipients had fewer deaths attributable to definite invasive fungal infection (1 of 15 vs. 6 of 15, respectively; P = .04) and achieved more frequent success without fungal colonization (52 [37%] of 141 vs. 27 [20% of 133, respectively; P = .004; relative risk reduction, 85%) than did placebo recipients. Patients benefiting the most from fluconazole prophylaxis included those with acute myeloid leukemia who were undergoing induction therapy with cytarabine plus anthracycline-based regimens and those receiving marrow autografts not supported with hematopoietic growth factors. Fluconazole prophylaxis reduces the incidence of superficial fungal infection and invasive fungal infection and fungal infection-related mortality among patients who are receiving intensive cytotoxic chemotherapy for remission induction.

Primary renal mucormycosis is a rare infection capable of acute illness with sepsis. Few cases have been reported. We report a case of an acute primary renal mucormycosis and review the published reports. The incidence of primary renal mucormycosis has risen in recent years. The most frequently reported underlying predisposing disorders are human immunodeficiency virus infection, intravenous drug abuse, and diabetes mellitus. Primary renal mucormycosis should be suspected in patients with an immunocompromising illness or particular risk factors, when persistent flank pain and fever with sterile urine not responding to appropriate antibiotics are associated with enlarged heterogeneous kidneys.

(1998). Vancomycin-Resistant Enterococcus. Scandinavian Journal of Gastroenterology: Vol. 33, No. 12, pp. 1233-1238.

The antimicrobial susceptibilities of 1058 Staphylococcus aureus and 2,163 coagulase-negative staphylococci (CNS) isolates obtained from clinical specimen between 1988 and 1995, were determined against 13 anti-staphylococcal antibiotics. During the study period the resistance of Staphylococcus aureus to ciprofloxacin, ceftazidime, and norfloxacin increased significantly by 7%, 4%, and 6%, respectively (por = 0.001). By comparison, the antibiotic resistance of CNS to ceftazidime, oxacillin, norfloxacin, ciprofloxacin, fusidic acid, and cefoxitin increased by 20%, 17%, 15%, 14%, 12% and 10%, respectively (por = 0.001). Invasive and noninvasive S. aureus had similar antibiotic resistance, whereas CNS invasive isolates were more resistant than noninvasive isolates to every antibiotics, except vancomycin and fusidic acid. These differences were significant (p0.001) for oxacillin, cefoxitin, and clindamycin. Our observations confirm that staphylococci and particularly CNS isolates show an important rate of increased resistance to the standard antimicrobials used for therapy, and that the rate of emergence of resistance differ considerably between coagulase-positive and coagulase-negative staphylococci.

We read with interest the recent paper by Wheat et al. ([1][1]) reporting on the long-term stability of Aspergillus galactomannan in bronchoalveolar lavage fluid (BALF) and serum specimens stored at −20°C. Their findings contrasted with previously published results from Johnson et al. ([2][2])

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.