Management of infectious disease syndromes in thoracic organ transplants and mechanical circulatory device recipients: a Delphi panel.

PURPOSE: Antimicrobial misuse contributes to antimicrobial resistance in thoracic transplant (TTx) and mechanical circulatory support (MCS) recipients. This study uses a modified Delphi method to define the expected appropriate antimicrobial prescribing for the common clinical scenarios encountered in TTx and MCS recipients. METHODS: An online questionnaire on managing 10 common infectious disease syndromes was submitted to a multidisciplinary Delphi panel of 25 experts from various disciplines. Consensus was predefined as 80% agreement for each question. Questions where consensus was not achieved were discussed during live virtual live sessions adapted by an independent process expert. RESULTS: An online survey of 62 questions related to 10 infectious disease syndromes was submitted to the Delphi panel. In the first round of the online questionnaire, consensus on antimicrobial management was reached by 6.5% (4/62). In Round 2 online live discussion, the remaining 58 questions were discussed among the Delphi Panel members using a virtual meeting platform. Consensus was reached among 62% (36/58) of questions. Agreement was not reached regarding the antimicrobial management of the following six clinical syndromes: (1) Burkholderia cepacia pneumonia (duration of therapy); (2) Mycobacterium abscessus (intra-operative antimicrobials); (3) invasive aspergillosis (treatment of culture-negative but positive BAL galactomannan) (duration of therapy); (4) respiratory syncytial virus (duration of antiviral therapy); (5) left ventricular assist device deep infection (initial empirical antimicrobial coverage) and (6) CMV (duration of secondary prophylaxis). CONCLUSION: This Delphi panel developed consensus-based recommendations for 10 infectious clinical syndromes seen in TTx and MCS recipients.

Update on therapeutic approaches for invasive fungal infections in adults.

Invasive fungal infections are increasingly encountered with the expansion of iatrogenic immunosuppression, including not only solid organ and hematopoietic stem cell transplant recipients but also patients with malignancies or autoimmune diseases receiving immunomodulatory therapies, such as Bruton Tyrosine Kinase (BTK) inhibitor. Their attributable mortality remains elevated, part of which is a contribution from globally emerging resistance in both molds and yeasts. Because antifungal susceptibility test results are often unavailable or delayed, empiric and tailored antifungal approaches including choice of agent(s) and use of combination therapy are heterogeneous and often based on clinician experience with knowledge of host's net state of immunosuppression, prior antifungal exposure, antifungal side effects and interaction profile, clinical severity of disease including site(s) of infection and local resistance data. In this review, we aim to summarize previous recommendations and most recent literature on treatment of invasive mold and yeast infections in adults to guide optimal evidence-based therapeutic approaches. We review the recent data that support use of available antifungal agents, including the different triazoles that have now been studied in comparison to previously preferred agents. We discuss management of complex infections with specific emerging fungi such as Scedosporium spp., Fusarium spp., Trichosporon asahii, and Candida auris. We briefly explore newer antifungal agents or formulations that are now being investigated to overcome therapeutic pitfalls, including but not limited to olorofim, rezafungin, fosmanogepix, and encochleated Amphotericin B. We discuss the role of surgical resection or debridement, duration of treatment, follow-up modalities, and need for secondary prophylaxis, all of which remain challenging, especially in patients chronically immunocompromised or awaiting more immunosuppressive therapies.

Impact of Language Barriers on Outcomes and Experience of COVID-19 Patients Hospitalized in Quebec, Canada, During the First Wave of the Pandemic.

Language barriers (LB) contribute to coronavirus disease 2019 (COVID-19) health inequities. People with LB were more likely to be SARS-CoV-2 positive despite lower testing and had higher rates of hospitalization. Data on hospital outcomes among immigrants with LB, however, are limited. We aimed to investigate the clinical outcomes of hospitalized COVID-19 cases by LB, immigration status, ethnicity, and access to COVID-19 health information and services prior to admission. Adults with laboratory-confirmed community-acquired COVID-19 hospitalized from March 1 to June 30, 2020, at four tertiary-care hospitals in Montréal, Quebec, Canada were included. Demographics, comorbidities, immigration status, country of birth, ethnicity, presence of LB, and hospital outcomes (ICU admission and death) were obtained through a chart review. Additional socio-economic and access to care questions were obtained through a phone survey. A Fine-Gray competing risk subdistribution hazards model was used to estimate the risk of ICU admission and in-hospital death by immigrant status, region of birth and LB Among 1093 patients, 622 (56.9%) were immigrants and 101 (16.2%) of them had a LB. One third (36%) of immigrants with LB did not have access to an interpreter during hospitalization. Admission to ICU and in-hospital mortality were not significantly different between groups. Prior to admission, one third (14/41) of immigrants with LB had difficulties accessing COVID-19 information in their mother tongue and one third (9/27) of non-white immigrants with a LB had difficulties accessing COVID-19 services. Immigrants with LB were inequitably affected by the first wave of the pandemic in Quebec, Canada. In our study, a large proportion had difficulties accessing information and services related to COVID-19 prior to admission, which may have increased SARS-CoV-2 exposure and hospitalizations. After hospitalization, a large proportion did not have access to interpreters. Providing medical information and care in the language of preference of increasing diverse populations in Canada is important for promoting health equity.

Real-World Effectiveness of Nirmatrelvir/Ritonavir on Coronavirus Disease 2019-Associated Hospitalization Prevention: A Population-based Cohort Study in the Province of Quebec, Canada.

BACKGROUND: Nirmatrelvir/ritonavir has shown to reduce COVID-19 hospitalization and death before Omicron, but updated real-world evidence studies are needed. This study aimed to assess whether nirmatrelvir/ritonavir reduces the risk of COVID-19-associated hospitalization among high-risk outpatients. METHODS: A retrospective cohort study of outpatients with SARS-CoV-2 between March 15 and 15 October 2022, using data from the Quebec clinico-administrative databases. Outpatients treated with nirmatrelvir/ritonavir were compared with infected ones not receiving nirmatrelvir/ritonavir using propensity-score matching. Relative risk (RR) of COVID-19-associated hospitalization within 30 days was assessed using a Poisson regression. RESULTS: A total of 8402 treated outpatients were matched to controls. Regardless of vaccination status, nirmatrelvir/ritonavir treatment was associated with a 69% reduced RR of hospitalization (RR: .31; 95% CI: .28; .36; number needed to treat [NNT] = 13). The effect was more pronounced in outpatients with incomplete primary vaccination (RR: .04; 95% CI: .03; .06; NNT = 8), while no benefit was found in those with a complete primary vaccination (RR: .93; 95% CI: .78; 1.08). Subgroups analysis among high-risk outpatients with a complete primary vaccination showed that nirmatrelvir/ritonavir treatment was associated with a significant decrease in the RR of hospitalization in severely immunocompromised outpatients (RR: .66; 95% CI: .50; .89; NNT = 16) and in high-risk outpatients aged ≥70 years (RR: .50; 95% CI: .34; .74; NNT = 10) when the last dose of the vaccine was received at least 6 months ago. CONCLUSIONS: Nirmatrelvir/ritonavir reduces the risk of COVID-19-associated hospitalization among incompletely vaccinated high-risk outpatients and among some subgroups of completely vaccinated high-risk outpatients.

Post-transplant outcomes among cystic fibrosis patients undergoing lung transplantation colonized by Burkholderia: A single center cohort study.

BACKGROUND: Prior infection with Burkholderia cepacia complex (BCC) has been associated with poorer outcomes after lung transplantation, posing an important dilemma for cystic fibrosis (CF). Although current guidelines consider BCC infection to be a relative contraindication, some centers continue to offer lung transplantation to BCC-infected CF patients. METHODS: We conducted a retrospective cohort study which included all consecutive CF-LTR between 2000 and 2019 to compare the postoperative survival of BCC-infected CF lung transplant recipients (CF-LTR) to BCC-uninfected patients. We used a Kaplan-Meier analysis to compare survival of BCC-infected to BCC-uninfected CF-LTR and fitted a multivariable Cox model, adjusted for age, sex, BMI and year of transplantation as potential confounders. As an exploratory analysis, Kaplan-Meier curves were also stratified by the presence of BCC and urgency of transplantation. RESULTS: A total of 205 patients were included with a mean age of 30.5 years. Seventeen patients (8%) were infected with BCC prior to LT. Patients were infected with the following species: B. multivorans5, B. vietnamiensis3, combined B. multivorans and B. vietnamiensis3 and others4. None of the patients were infected with B. cenocepacia. Three patients were infected with B. gladioli. One-year survival was 91.7% (188/205) for the entire cohort, 82.4% (14/17) among BCC-infected CF-LTR, and 92.5% (173/188) among BCC uninfected CF-LTR (crude HR = 2.19; 95%CI 0.99-4.85; p = 0.05). In the multivariable model, presence of BCC was not significantly associated with worse survival (adjusted HR 1.89; 95%CI 0.85-4.24; p = 0.12). In the stratified analysis for both presence of BCC and urgency of transplantation, urgency of transplantation among BCC-infected CF-LTR appeared to be associated with poorer outcome (p = 0.003 across the 4 subgroups). CONCLUSION: Our results suggest that non-cenocepacia BCC-infected CF-LTR have comparable survival rate to BCC-uninfected CF-LTR.

In-hospital outcomes of SARS-CoV-2-infected health care workers in the COVID-19 pandemic first wave, Quebec, Canada.

BACKGROUND: Health care workers (HCW), particularly immigrants and ethnic minorities are at increased risk for SARS-CoV-2 infection. Outcomes during a COVID-19 associated hospitalization are not well described among HCW. We aimed to describe the characteristics of HCW admitted with COVID-19 including immigrant status and ethnicity and the associated risk factors for Intensive Care unit (ICU) admission and death. METHODS: Adults with laboratory-confirmed community-acquired COVID-19 hospitalized from March 1 to June 30, 2020, at four tertiary-care hospitals in Montréal, Canada were included. Demographics, comorbidities, occupation, immigration status, country of birth, ethnicity, workplace exposures, and hospital outcomes (ICU admission and death) were obtained through a chart review and phone survey. A Fine and Gray competing risk proportional hazards model was used to estimate the risk of ICU admission among HCW stratified by immigrant status and region of birth. RESULTS: Among 1104 included persons, 150 (14%) were HCW, with a phone survey participation rate of 68%. HCWs were younger (50 vs 64 years; p<0.001), more likely to be female (61% vs 41%; p<0.001), migrants (68% vs 55%; p<0.01), non-White (65% vs 41%; p<0.001) and healthier (mean Charlson Comorbidity Index of 0.3 vs 1.2; p<0.001) compared to non-HCW. They were as likely to be admitted to the ICU (28% vs 31%; p = 0.40) but were less likely to die (4% vs. 17%; p<0.001). Immigrant HCW accounted for 68% of all HCW cases and, compared to Canadian HCW, were more likely to be personal support workers (PSW) (54% vs. 33%, p<0.01), to be Black (58% vs 4%) and to work in a Residential Care Facility (RCF) (59% vs 33%; p = 0.05). Most HCW believed that they were exposed at work, 55% did not always have access to personal protective equipment (PPE) and 40% did not receive COVID-19-specific Infection Control (IPAC) training. CONCLUSION: Immigrant HCW were particularly exposed to COVID-19 infection in the first wave of the pandemic in Quebec. Despite being young and healthy, one third of all HCW required ICU admission, highlighting the importance of preventing workplace transmission through strong infection prevention and control measures, including high COVID-19 vaccination coverage.

A consensus conference to define the utility of advanced infectious disease diagnostics in solid organ transplant recipients.

The last decade has seen an explosion of advanced assays for the diagnosis of infectious diseases, yet evidence-based recommendations to inform their optimal use in the care of transplant recipients are lacking. A consensus conference sponsored by the American Society of Transplantation (AST) was convened on December 7, 2021, to define the utility of novel infectious disease diagnostics in organ transplant recipients. The conference represented a collaborative effort by experts in transplant infectious diseases, diagnostic stewardship, and clinical microbiology from centers across North America to evaluate current uses, unmet needs, and future directions for assays in 5 categories including (1) multiplex molecular assays, (2) rapid antimicrobial resistance detection methods, (3) pathogen-specific T-cell reactivity assays, (4) next-generation sequencing assays, and (5) mass spectrometry-based assays. Participants reviewed and appraised available literature, determined assay advantages and limitations, developed best practice guidance largely based on expert opinion for clinical use, and identified areas of future investigation in the setting of transplantation. In addition, attendees emphasized the need for well-designed studies to generate high-quality evidence needed to guide care, identified regulatory and financial barriers, and discussed the role of regulatory agencies in facilitating research and implementation of these assays. Findings and consensus statements are presented.

Voriconazole therapeutic drug monitoring among lung transplant recipients receiving targeted therapy for invasive aspergillosis.

BACKGROUND: Voriconazole is the first line treatment for invasive aspergillosis (IA) Current guidelines suggest performing regular voriconazole therapeutic drug monitoring (TDM) to optimize treatment efficacy. We aimed to determine if TDM was predictive of clinical outcome in LTRs. METHODS: Retrospective chart review was performed for all LTRs with probable or proven IA, treated with voriconazole monotherapy and who underwent TDM during therapy. Clinical outcome and toxicity were measured at 12 weeks. Classification and regression tree (CART) analysis was used to determine the most predictive voriconazole level thresholds for successful outcome. RESULTS: One hundred and eighteen TDM samples from 30 LTRs with IA were analyzed. Three LTRs were excluded due to early treatment discontinuation. The median TDM level was 1.2 µg/ml (range 0.06-7.3). At 12 weeks, 62% (17/27) of patients had a successful outcome, while 37% (10/27) of patients failed therapy. CART analysis determined that the best predictor for successful outcome was a median TDM level >0.72 µg/ml. Seventy percent (14/20) of patients with median TDM above 0.72 µg/ml had a successful outcome, compared to 42.9% (3/7) of patients with a median TDM below 0.72 µg/ml (OR 3.11; 95% CI: 0.53-20.4; P = 0.21). CART analysis determined that a TDM level greater than 2.13 µg/ml was predictive of hepatotoxicity. CONCLUSIONS: Our data suggests that a voriconazole TDM range between 0.72 µg/ml and 2.13 µg/ml may be associated with improved outcomes. Our study is in line with current recommendations on the use of voriconazole TDM in improving outcome and minimizing toxicity in LTR with IA.

Outcomes of hospitalized COVID-19 patients in Canada: impact of ethnicity, migration status and country of birth.

BACKGROUND: Ethnoracial groups in high-income countries have a 2-fold higher risk of SARS-CoV-2 infection, associated hospitalizations, and mortality than Whites. Migrants are an ethnoracial subset that may have worse COVID-19 outcomes due to additional barriers accessing care, but there are limited data on in-hospital outcomes. We aimed to disaggregate and compare COVID-19 associated hospital outcomes by ethnicity, immigrant status and region of birth. METHODS: Adults with community-acquired SARS-CoV-2 infection, hospitalized March 1-June 30, 2020, at four hospitals in Montréal, Quebec, Canada, were included. Age, sex, socioeconomic status, comorbidities, migration status, region of birth, self-identified ethnicity [White, Black, Asian, Latino, Middle East/North African], intensive care unit (ICU) admissions and mortality were collected. Adjusted hazard ratios (aHR) for ICU admission and mortality by immigrant status, ethnicity and region of birth adjusted for age, sex, socioeconomic status and comorbidities were estimated using Fine and Gray competing risk models. RESULTS: Of 1104 patients (median [IQR] age, 63.0 [51.0-76.0] years; 56% males), 57% were immigrants and 54% were White. Immigrants were slightly younger (62 vs 65 years; p = 0.050), had fewer comorbidities (1.0 vs 1.2; p < 0.001), similar crude ICU admissions rates (33.0% vs 28.2%) and lower mortality (13.3% vs 17.6%; p < 0.001) than Canadian-born. In adjusted models, Blacks (aHR 1.39, 95% confidence interval 1.05-1.83) and Asians (1.64, 1.15-2.34) were at higher risk of ICU admission than Whites, but there was significant heterogeneity within ethnic groups. Asians from Eastern Asia/Pacific (2.15, 1.42-3.24) but not Southern Asia (0.97, 0.49-1.93) and Caribbean Blacks (1.39, 1.02-1.89) but not SSA Blacks (1.37, 0.86-2.18) had a higher risk of ICU admission. Blacks had a higher risk of mortality (aHR 1.56, p = 0.049). CONCLUSIONS: Data disaggregated by region of birth identified subgroups of immigrants at increased risk of COVID-19 ICU admission, providing more actionable data for health policymakers to address health inequities.

Multicenter Evaluation of Attenuated Total Reflectance Fourier Transform Infrared (ATR-FTIR) Spectroscopy-Based Method for Rapid Identification of Clinically Relevant Yeasts.

Fourier transform infrared (FTIR) spectroscopy has demonstrated applicability as a reagent-free whole-organism fingerprinting technique for both microbial identification and strain typing. For routine application of this technique in microbiology laboratories, acquisition of FTIR spectra in the attenuated total reflectance (ATR) mode simplifies the FTIR spectroscopy workflow, providing results within minutes after initial culture without prior sample preparation. In our previous central work, 99.7% correct species identification of clinically relevant yeasts was achieved by employing an ATR-FTIR-based method and spectral database developed by our group. In this study, ATR-FTIR spectrometers were placed in 6 clinical microbiology laboratories over a 16-month period and were used to collect spectra of routine yeast isolates for on-site identification to the species level. The identification results were compared to those obtained from conventional biochemical tests and/or matrix-assisted laser desorption/ionization-time of flight mass spectrometry. Isolates producing discordant results were reanalyzed by routine identification methods, ATR-FTIR spectroscopy, and PCR gene sequencing of the D1/D2 and internal transcribed spacer (ITS) regions. Among the 573 routine clinical yeast isolates collected and identified by the ATR-FTIR-based method, 564 isolates (98.4%) were correctly identified at the species level, while the remaining isolates were inconclusive with no misidentifications. Due to the low prevalence of Candida auris in routine isolates, additional randomly selected C. auris (n = 24) isolates were obtained for evaluation and resulted in 100% correct identification. Overall, the data obtained in our multicenter evaluation study using multiple spectrometers and system operators indicate that ATR-FTIR spectroscopy is a reliable, cost-effective yeast identification technique that provides accurate and timely (∼3 min/sample) species identification promptly after the initial culture.

Clinical Practice Guideline for Solid Organ Donation and Transplantation During the COVID-19 Pandemic.

The coronavirus 2019 (COVID-19) pandemic has disrupted health systems worldwide, including solid organ donation and transplantation programs. Guidance on how best to screen patients who are potential organ donors to minimize the risks of COVID-19 as well as how best to manage immunosuppression and reduce the risk of COVID-19 and manage infection in solid organ transplant recipients (SOTr) is needed. METHODS: Iterative literature searches were conducted, the last being January 2021, by a team of 3 information specialists. Stakeholders representing key groups undertook the systematic reviews and generation of recommendations using a rapid response approach that respected the Appraisal of Guidelines for Research and Evaluation II and Grading of Recommendations, Assessment, Development and Evaluations frameworks. RESULTS: The systematic reviews addressed multiple questions of interest. In this guidance document, we make 4 strong recommendations, 7 weak recommendations, 3 good practice statements, and 3 statements of "no recommendation." CONCLUSIONS: SOTr and patients on the waitlist are populations of interest in the COVID-19 pandemic. Currently, there is a paucity of high-quality evidence to guide decisions around deceased donation assessments and the management of SOTr and waitlist patients. Inclusion of these populations in clinical trials of therapeutic interventions, including vaccine candidates, is essential to guide best practices.

Targeted caspofungin prophylaxis for invasive aspergillosis in high-risk liver transplant recipients, a single-center experience.

BACKGROUND: Invasive aspergillosis (IA) is a rare but highly lethal complication after orthotopic liver transplantation (OLT). Targeted antifungal prophylaxis has been proposed as a strategy to prevent IA among orthotopic liver transplant recipient (OLTr), but limited data are available to support its efficacy. METHOD: We conducted a single-center, retrospective, before and after cohort study, comparing IA incidences among OLTr who did not receive antifungal prophylaxis after transplantation (cohort 1) to OLTr who received targeted antifungal prophylaxis after liver transplantation (cohort 2). Patients in cohort 2 received caspofungin prophylaxis if they presented one of the following risk factors: retransplantation, acute liver failure, dialysis, or Aspergillus colonization prior to transplantation. The primary outcome was IA at 90 days after transplantation. RESULTS: A total of 391 OLTr were included in the study; 181 patients in the cohort 1 (no prophylaxis) and 210 patients in the cohort 2 (targeted prophylaxis). Among patients in cohort 2, 19% (40/ 210) were considered at high risk for IA and 85% (34/40) of those received caspofungin prophylaxis. The incidence of IA at 90 days was 3.3% (6/ 181) and 0.5% (1/ 210), in cohort 1 and 2, respectively (OR 0.14; 95%CI 0.01-0.83; P = .03). Ninety-day mortality was similar among the two cohorts (3.9% (7/181) and 2.4% (5/210) in cohort 1 and 2, respectively (OR 0.61; 95% 0.18-1.93; P = .40)). The 90-day mortality among the OLTs with IA was 71% (5/7). CONCLUSION: Targeted caspofungin prophylaxis was associated with lower rate of IA.

Pulmonary mucormycosis in a patient with acute liver failure: A case report and systematic review of the literature.

PURPOSE: Pulmonary mucormycosis is a highly lethal invasive fungal infection usually found in immunocompromised patients. We report herein the case of an adult woman who developed pulmonary mucormycosis with possible systemic dissemination after recovering from acute liver failure secondary to acetaminophen overdose. RESULTS: Our case developed an invasive pulmonary mucormycosis with probable systemic dissemination. She did not suffer from any immunocompromising disease other than severe acute liver failure. She did not survive the disease, although she received appropriate antifungal treatment. We also performed a systematic review of the literature on pulmonary mucormycosis, with or without dissemination, in immunocompetent patients. We found 16 cases of pulmonary or disseminated mucormycosis in immunocompetent patients. Fifty-seven percent of them died and none occurred after an acute liver failure episode. CONCLUSION: This case report is the first one to present an invasive pulmonary mucormycosis infection after acute liver failure in an adult patient. The clinical course of this disease is highly lethal, even in immunocompetent adults.

Identification of Candida auris by Use of the Updated Vitek 2 Yeast Identification System, Version 8.01: a Multilaboratory Evaluation Study.

Candida auris is an emerging multidrug-resistant yeast that has been systematically incorrectly identified by phenotypic methods in clinical microbiology laboratories. The Vitek 2 automated identification system (bioMérieux) recently included C. auris in its database (version 8.01). We evaluated the performance of the Vitek 2 YST ID card to identify C. auris and related species. A panel of 44 isolates of Candida species (C. auris, n = 35; Candida haemulonii, n = 5; Candida duobushaemulonii, n = 4) were tested by three different hospital-based microbiology laboratories. Among 35 isolates of C. auris, Vitek 2 yielded correct identification in an average of 52% of tested samples. Low-discrimination (LD) results with an inability to distinguish between C. auris, C. duobushaemulonii, and Candida famata were obtained in an average of 27% of samples. Incorrect identification results were obtained in an average of 21% of samples, the majority (91%) of which were reported as C. duobushaemulonii and the remaining 9% of which were reported as Candida lusitaniae/C. duobushaemulonii. The proportion of correct identification was not statistically different across different centers (P = 0.78). Stratification by genetic clades demonstrated that 100% (n = 8) of the strains of the South American clade were correctly identified compared to 7% (n = 10) and 0% (n = 4) from the African and East Asian clades, respectively. None of the non-auris Candida strains (n = 9) were incorrectly identified as C. auris Our results show that the Vitek 2 (version 8.01) yeast identification system has a limited ability to correctly identify C. auris These data suggest that an identification result for C. duobushaemulonii should warrant further testing to rule out C. auris The overall performance of the Vitek 2 seems to differ according to C. auris genetic clade, with the South American isolates yielding the most accurate results.

Hiding in plain sight: A case of fever, rash, and jaundice.

A 25-year-old man presented to the emergency department with a 3-day history of fever, anorexia, jaundice, and a generalized skin eruption. His liver function tests showed marked cholestatic and cytolytic abnormalities without liver insufficiency. A liver biopsy was performed, and morphology with routine stains was considered non-specific. Because of the dermatological findings, the non-specific biopsy morphology, and the absence of an identified infectious etiology, a diagnosis of Kawasaki disease was presumed. However, additional colorations on liver biopsy with Warthin-Starry stain revealed multiple thin and coiled microorganisms compatible with spirochetes. His serology for leptospirosis was found to be positive for IgM, supporting the diagnosis of acute leptospirosis with liver involvement. Our case illustrates the diagnostic challenge of leptospirosis and highlights the utility of conventional laboratory tests to confirm the diagnosis. Exceptionally, Warthin-Starry stain allowed the identification of leptospires in liver biopsy and confirmed liver involvement of systemic leptospirosis.

Un homme de 25 ans a consulté à l'urgence parce qu'il faisait de la fièvre depuis trois jours, de l'anorexie, un ictère et une éruption cutanée généralisée. Les tests de fonction hépatique ont révélé des anomalies cholestatiques et cytolytiques marquées, sans insuffisance hépatique. La coloration standard de la biopsie hépatique a révélé une morphologie cellulaire considérée comme non spécifique. Compte tenu des observations dermatologiques, de la morphologie non spécifique de la biopsie et de l'absence d'étiologie infectieuse établie, un diagnostic de maladie de Kawasaki a été présumé. Cependant, l'ajout d'une coloration de Warthin-Starry a révélé de multiples microorganismes minces et torsadés compatibles avec des spirochètes. La sérologie pour la leptospirose s'est avérée positive pour les anticorps IgM, appuyant un diagnostic de leptospirose aiguë avec atteinte hépatique. Ce cas illustre les difficultés diagnostiques de la leptospirose et fait ressortir l'utilité des tests de laboratoire traditionnels pour confirmer le diagnostic. Exceptionnellement, la coloration de Warthin­Starry a permis d'observer des leptospires à la biopsie hépatique et confirmé la leptospirose systémique avec atteinte hépatique.

Utility of voriconazole therapeutic drug monitoring: a meta-analysis.

BACKGROUND: Voriconazole therapeutic drug monitoring (TDM) is increasingly used in clinical practice. However, the utility of voriconazole TDM to guide therapy remains uncertain and controversial. We conducted a meta-analysis of studies assessing the relationship between voriconazole serum concentration and clinical outcomes of success and toxicity. METHODS: We searched bibliographic databases for studies on voriconazole serum concentrations and clinical outcomes. We compared success outcomes between patients with therapeutic and subtherapeutic voriconazole serum concentrations, and toxicity outcomes between patients with and without supratherapeutic serum concentrations. RESULTS: Twenty-four studies were analysed. Pooled analysis for efficacy endpoint demonstrated that patients with therapeutic voriconazole serum concentrations (1.0-2.2 mg/L) were more likely to have successful outcomes compared with those with subtherapeutic voriconazole serum concentrations (OR 2.30; 95% CI 1.39-3.81). A therapeutic threshold of 1.0 mg/L was most predictive of successful outcome (OR 1.94; 95% CI 1.04-3.62). Patients with therapeutic concentrations did not have better survival rates. Pooled analysis for toxicity endpoint demonstrated that patients with supratherapeutic voriconazole serum concentrations (4.0-6.0 mg/L) were at increased risk of toxicity (OR 4.17; 95% CI 2.08-8.36). A supratherapeutic threshold of 6.0 mg/L was most predictive of toxicity (OR 4.60; 95% CI 1.49-14.16). CONCLUSIONS: Patients with therapeutic voriconazole serum concentrations were twice as likely to achieve successful outcomes. The likelihood of toxicity associated with supratherapeutic voriconazole serum concentrations was 4-fold that of therapeutic concentrations. Our findings suggest that the use of voriconazole TDM to aim for serum concentrations between 1.0 and 6.0 mg/L during therapy may be warranted to optimize clinical success and minimize toxicity.