Breakthrough Invasive Fungal Infections in Patients With High-Risk Hematological Disorders Receiving Voriconazole and Posaconazole Prophylaxis: A Systematic Review.

BACKGROUND: Primary antifungal prophylaxis with mold-active azoles is used to prevent invasive fungal infections in patients with high-risk hematological disorders; however, breakthrough infections occur, and the reasons for treatment failure are still not fully understood. To help inform clinical decisions, we sought to define microbiological, clinical, and pharmacological characteristics of proven and probable breakthrough invasive fungal infections (bIFIs) in patients with high-risk hematological disorders receiving voriconazole or posaconazole prophylaxis. METHODS: We performed a systematic review of the literature following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The search strategy was last conducted on 19 April 2023. RESULTS: We assessed 5293 studies for eligibility, and 300 were selected for data extraction. These studies described 1076 cases of bIFIs occurring under voriconazole (42.5%) or posaconazole (57.5%). The most commonly found pathogens were Aspergillus (40%), Mucorales (20%), Candida (18%), and Fusarium (9%) species. Mucorales were more frequent among voriconazole-emerging cases, whereas Aspergillus and Fusarium were more prevalent among posaconazole-emerging cases. Definitive, putative, or probable antifungal resistance was found in 31% of cases. Therapeutic drug monitoring showed subtherapeutic azole concentration in 32 of 90 (36%) cases. Infection-related mortality was reported in 117 cases and reached 35%. CONCLUSIONS: In our systemic review, the most common bIFIs were aspergillosis, mucormycosis, candidiasis, and fusariosis. Antifungal resistance explains only a minority of cases. Subtherapeutic prophylaxis was frequent but rarely reported. Prospective studies are needed to better understand these infections and to establish optimal management.

Mortality associated with Blastomyces dermatitidis infection: A systematic review of the literature and meta-analysis.

Published case fatality in blastomycosis patients ranges between 4% and 78%. This study aimed to assess mortality associated with blastomycosis and identify its associated risk factors. We conducted a systematic review of publications related to Blastomyces dermatitidis available in PubMed and Scopus databases. Studies that reported data on blastomycosis mortality and that were published from inception through February 2018 were assessed and included in the analysis. Using the R meta package, a random-effect model meta-analysis was used to calculate pooled and stratified estimates of case-fatality proportions and risk ratios. Of 1553 publications, we included 20 studies reporting on a total of 2820 cases of blastomycosis between 1970 and 2014 and three case series reports with 10, 21, and 36 patients. The mean or median ages ranged from 28 to 59 years. Mortality was defined as attributable mortality caused by blastomycosis in 13 studies. Among 14 studies with a standard error ≤0.05, the overall pooled mortality was 6.6% (95% confidence interval [CI], 4.9-8.2) with 57% heterogeneity. The mortality rate was 37% (95% CI, 23-51) in immunocompromised patients and 75% (95% CI, 53-96) in patients who developed an acute respiratory distress syndrome (ARDS) (n = 3 studies each). ARDS was the only identified risk factor in general patients (risk ratio = 10.2). The overall mortality was significantly higher in studies involving immunocompromised patients and ARDS patients. Our analysis showed considerable heterogeneity among studies. Inconsistent mortality definitions may have contributed to the observed heterogeneity. Further research is needed to assess potential risk factors for mortality.

Multilocus Variable-Number Tandem-Repeat Analysis of Clostridioides difficile Clusters in Ribotype 027 Isolates and Lack of Association with Clinical Outcomes.

The epidemiology of Clostridioides difficile infection (CDI) has drastically changed since the emergence of the epidemic strain BI/NAP1/027, also known as ribotype 027 (R027). However, the relationship between the infecting C. difficile strain and clinical outcomes is still debated. We hypothesized that certain subpopulations of R027 isolates could be associated with unfavorable outcomes. We applied high-resolution multilocus variable-number tandem-repeat analysis (MLVA) to characterize C. difficile R027 isolates collected from confirmed CDI patients recruited across 10 Canadian hospitals from 2005 to 2008. PCR ribotyping was performed first to select R027 isolates that were then analyzed by MLVA (n = 450). Complicated CDI (cCDI) was defined by the occurrence of any of admission to an intensive care unit, colonic perforation, toxic megacolon, colectomy, and if CDI was the cause or contributed to death within 30 days after enrollment. Three major MLVA clusters were identified, MC-1, MC-3, and MC-10. MC-1 and MC-3 were exclusive to Quebec centers, while MC-10 was found only in Ontario. Fewer cases infected with MC-1 developed cCDI (4%) than those infected with MC-3 and MC-10 (15% and 16%, respectively), but a statistically significant difference was not reached. Our data did not identify a clear association between subpopulations of R027 and different clinical outcomes; however, the data confirmed the utility of MLVA's higher discrimination potential to better characterize CDI populations in an epidemiological analysis. For a patient with CDI, the progression toward an unfavorable outcome is a complex process that probably includes several interrelated strain and host characteristics.

The effectiveness and cost-effectiveness of screening for latent tuberculosis among migrants in the EU/EEA: a systematic review.

BackgroundMigrants account for a large and growing proportion of tuberculosis (TB) cases in low-incidence countries in the European Union/European Economic Area (EU/EEA) which are primarily due to reactivation of latent TB infection (LTBI). Addressing LTBI among migrants will be critical to achieve TB elimination. Methods: We conducted a systematic review to determine effectiveness (performance of diagnostic tests, efficacy of treatment, uptake and completion of screening and treatment) and a second systematic review on cost-effectiveness of LTBI screening programmes for migrants living in the EU/EEA. Results: We identified seven systematic reviews and 16 individual studies that addressed our aims. Tuberculin skin tests and interferon gamma release assays had high sensitivity (79%) but when positive, both tests poorly predicted the development of active TB (incidence rate ratio: 2.07 and 2.40, respectively). Different LTBI treatment regimens had low to moderate efficacy but were equivalent in preventing active TB. Rifampicin-based regimens may be preferred because of lower hepatotoxicity (risk ratio = 0.15) and higher completion rates (82% vs 69%) compared with isoniazid. Only 14.3% of migrants eligible for screening completed treatment because of losses along all steps of the LTBI care cascade. Limited economic analyses suggest that the most cost-effective approach may be targeting young migrants from high TB incidence countries. Discussion: The effectiveness of LTBI programmes is limited by the large pool of migrants with LTBI, poorly predictive tests, long treatments and a weak care cascade. Targeted LTBI programmes that ensure high screening uptake and treatment completion will have greatest individual and public health benefit.

The effectiveness and cost-effectiveness of screening for active tuberculosis among migrants in the EU/EEA: a systematic review.

BACKGROUND: The foreign-born population make up an increasing and large proportion of tuberculosis (TB) cases in European Union/European Economic Area (EU/EEA) low-incidence countries and challenge TB elimination efforts. Methods: We conducted a systematic review to determine effectiveness (yield and performance of chest radiography (CXR) to detect active TB, treatment outcomes and acceptance of screening) and a second systematic review on cost-effectiveness of screening for active TB among migrants living in the EU/EEA. Results: We identified six systematic reviews, one report and three individual studies that addressed our aims. CXR was highly sensitive (98%) but only moderately specific (75%). The yield of detecting active TB with CXR screening among migrants was 350 per 100,000 population overall but ranged widely by host country (110-2,340), migrant type (170-1,192), TB incidence in source country (19-336) and screening setting (220-1,720). The CXR yield was lower (19.6 vs 336/100,000) and the numbers needed to screen were higher (5,076 vs 298) among migrants from source countries with lower TB incidence (≤ 50 compared with ≥ 350/100,000). Cost-effectiveness was highest among migrants originating from high (> 120/100,000) TB incidence countries. The foreign-born had similar or better TB treatment outcomes than those born in the EU/EEA. Acceptance of CXR screening was high (85%) among migrants. Discussion: Screening programmes for active TB are most efficient when targeting migrants from higher TB incidence countries. The limited number of studies identified and the heterogeneous evidence highlight the need for further data to inform screening programmes for migrants in the EU/EEA.

Risk of Active Tuberculosis in Patients with Cancer: A Systematic Review and Meta-Analysis.

Background: Cancer is a known risk factor for developing active tuberculosis (TB). We determined the incidence and relative risk of active TB in cancer patients compared to the general population. Methods: Electronic databases were searched up to December 2015: Medline, Medline InProcess, EMBASE, PubMed, the Cochrane Database of Systematic Reviews, Cancerlit, and Web of Science. Studies of pathologically confirmed cancer patients were included if active TB was identified concurrently or after the diagnosis. Cumulative incidence rate/100,000 population (CIR) of new cases of TB occurring in cancer patients and comparative incidence rate ratios (IRR) to the general population from the same country of origin were estimated. A random effect meta-analysis was conducted on the CIR and IRR. Results: A total of 23 studies reporting 593 TB cases occurring in 324,041 cancer patients between 1950 and 2011 were identified. In a meta-analysis of 6 studies conducted in the US in 317,243 cancer patients (98% of all patients) the CIR of active TB decreased by 3 fold and 6.5 fold in hematologic and solid cancers respectively before and after 1980. After 1980 the CIR of active TB was highest in hematologic (219/100,000 population, IRR=26), head and neck (143; 16), lung cancers (83; 9) and was lowest in breast and other solid cancers (38; 4). Conclusions: Individuals living in the US with hematologic, head and neck, and lung cancers had a 9-fold higher rate of developing active TB compared to those without cancer and would benefit from targeted latent TB screening and therapy.

A population-based study of chronic hepatitis C in immigrants and non-immigrants in Quebec, Canada.

BACKGROUND: Immigrants originating from intermediate and high HCV prevalence countries may be at increased risk of exposure to hepatitis C infection (HCV) in their countries of origin, however they are not routinely screened after arrival in most low HCV prevalence host countries. We aimed to describe the epidemiology of HCV in immigrants compared to the Canadian born population. METHODS: Using the reportable infectious disease database linked to the landed immigration database and several provincial administrative databases, we assembled a cohort of all reported cases of HCV in Quebec, Canada (1998-2008). Underlying co-morbidities were identified in the health services databases. Stratum specific rates of reported cases/100,000, rate ratios (RRs) and trends over the study period were estimated. RESULTS: A total of 20,862 patients with HCV were identified, among whom 1922 (9.2%) were immigrants. Immigrants were older and diagnosed a mean of 9.8 ± 7 years after arrival. The Canadian born population was more likely to have behavior co-morbidities (problematic alcohol or drug use) and HIV co-infection. Immigrants from Sub-Saharan Africa, Asia and Eastern Europe had the highest HCV reported rates with RRs compared to non-immigrants ranging from 1.5 to 1.7. The age and sex adjusted rates decreased by 4.9% per year in non-immigrants but remained unchanged in immigrants. The proportion of HCV occurring in immigrants doubled over the study period from 5 to 11%. CONCLUSIONS: Immigrants from intermediate and high HCV prevalence countries are at increased risk for HCV and had a mean delay in diagnosis of almost 10 years after arrival suggesting that they may benefit from targeted HCV screening and earlier linkage to care.

Clinical and Healthcare Burden of Multiple Recurrences of Clostridium difficile Infection.

BACKGROUND: Clostridium difficile infection (CDI) is associated with a high risk of recurrence (rCDI). Few studies have focused on multiple recurrences. To evaluate the potential of novel treatments targeting recurrence, we assessed the burden and severity of rCDI. METHODS: This was a retrospective cohort of adults diagnosed with CDI in a hospital in Sherbrooke, Canada (1998-2013). An rCDI episode was defined by the reappearance of diarrhea leading to a treatment, with or without a positive toxin assay, within 14-60 days after the previous episode. RESULTS: We included 1527 patients. The probability of developing a first rCDI was 25% (354/1418); a second, 38% (128/334); a third, 29% (35/121); and a fourth or more, 27% (9/33). Two or more rCDIs were observed in 9% (128/1389) of patients. The risk of a first recurrence fluctuated over time, but there was no such variation for second or further recurrences. The proportion of severe cases decreased (47% for initial episodes, 31% for first recurrences, 25% for second, 17% for third), as did the risk of complicated CDI (5.8% to 2.8%). The severity and risk of complications of first recurrences decreased over time, while oral vancomycin was used more systemically. A hospital admission was needed for 34% (148/434) of recurrences. CONCLUSIONS: This study documented the clinical and healthcare burden of rCDI: 34% of patients with rCDI needed admission, 28% developed severe CDI, and 4% developed a complication. Secular changes in the severity of recurrences could reflect variations in the predominant strain, or better management.

Factors Associated With Complications of Clostridium difficile Infection in a Multicenter Prospective Cohort.

BACKGROUND: Clostridium difficile infection (CDI) is the most common cause of nosocomial infectious diarrhea and may result in severe complications including death. We conducted a prospective study to identify risk factors for complications of CDI (cCDI). METHODS: Adult inpatients with confirmed CDI in 10 Canadian hospitals were enrolled and followed for 90 days. Potential risk factors were measured within 24 hours of diagnosis. Isolates were typed by polymerase chain reaction ribotyping. cCDI was defined as 1 or more of the following: colonic perforation, toxic megacolon, colectomy, admission to an intensive care unit for cCDI, or if CDI contributed to death within 30 days of enrollment. Risk factors for cCDI were investigated by logistic regression. RESULTS: A total of 1380 patients were enrolled. cCDI was observed in 8% of patients. The ribotype was identified in 922 patients, of whom 52% were infected with R027. Age ≥ 80 years, heart rate >90/minute, respiratory rate >20/minute, white cell count <4 × 10(9)/L or ≥ 20 × 10(9)/L, albumin <25 g/L, blood urea nitrogen >7 mmol/L, and C-reactive protein ≥ 150 mg/L were independently associated with cCDI. A higher frequency of cCDI was observed among R027-infected patients (10.9% vs 7.2%), but the association was not significant in adjusted analysis. CONCLUSIONS: CDI complications were associated with older age, abnormal blood tests, and abnormal vital signs. These factors, which are readily available to clinicians at the time of diagnosis, could be used for outcome prediction and risk stratification to select patients who may need closer monitoring or more aggressive therapy.

The Strain and the Clinical Outcome of Clostridioides difficile Infection: A Meta-analysis.

Background: The association between bacterial strains and clinical outcomes in Clostridioides difficile infection (CDI) has yielded conflicting results across studies. We conducted a systematic review and meta-analyses to assess the impact of these strains. Methods: Five electronic databases were used to identify studies reporting CDI severity, complications, recurrence, or mortality according to strain type from inception to June 2022. Random effect meta-analyses were conducted to assess outcome proportions and risk ratios (RRs). Results: A total of 93 studies were included: 44 reported recurrences, 50 reported severity or complications, and 55 reported deaths. Pooled proportions of complications were statistically comparable between NAP1/BI/R027 and R001, R078, and R106. Pooled attributable mortality was 4.8% with a gradation in patients infected with R014/20 (1.7%), R001 (3.8%), R078 (5.3%), and R027 (10.2%). Higher 30-day all-cause mortality was observed in patients infected with R001, R002, R027, and R106 (range, 20%-25%).NAP1/BI/R027 was associated with several unfavorable outcomes: recurrence 30 days after the end of treatment (pooled RR, 1.98; 95% CI, 1.02-3.84); admission to intensive care, colectomy, or CDI-associated death (1.88; 1.09-3.25); and 30-day attributable mortality (1.96; 1.23-3.13). The association between harboring the binary toxin gene and 30-day all-cause mortality did not reach significance (RR, 1.6 [0.9-2.9]; 7 studies). Conclusions: Numerous studies were excluded due to discrepancies in the definition of the outcomes and the lack of reporting of important covariates. NAP1/BI/R027, the most frequently reported and assessed strain, was associated with unfavorable outcomes. However, there were not sufficient data to reach significant conclusions on other strains.

Respiratory syncytial virus-related hospital stays in adults in France from 2012 to 2021: A national hospital database study.

BACKGROUND: Respiratory syncytial virus (RSV) causes lower respiratory tract infections (LRTI) that may lead to hospitalization or death. The present study aimed to assess the burden of RSV infections in hospitalized adults. METHODS: RSV-related hospitalizations were identified from the nationwide hospital claims database in France (PMSI) from 2012 to 2021 using ICD-10 codes J12.1, J20.5, J21.0 or B97.4, and outcomes assessment focused on 2016-2020. In-hospital outcomes included length of stay, need for intensive care (ICU) and in-hospital all-cause mortality. Post-discharge outcomes included 30-day readmission for decompensation, 90-day RSV-related readmission, and 30 and 60-day in-hospital mortality. RESULTS: A cumulated number of 17 483 RSV-related stays were identified representing a rate of 72.0 cases per million stays. The outcomes assessment included 12,987 patients: 55.8 % were females and the mean age was 74.1 ± 16.4 years, with 57 % ≥ 75 years. Most of patients (78.6 %) had at least one comorbidity, mainly chronic respiratory (56.3 %) and cardiovascular diseases (41.3 %), or diabetes (23.5 %). A co-infection was found in 22.4 %, primarily bacterial (12 %). The mean length of stay was 12.3 ± 13.1 days. Overall, 10.9 % were admitted to an ICU and in-hospital mortality was 7.3 %. In-hospital outcomes were higher in cases of co-infection. Among 12 033 patients alive at discharge from the index stay, 6.5 % were readmitted with RSV within 90 days, 8.1 % for decompensation within 30 days, and 5.6 % died within 60-day. CONCLUSION: This study demonstrated the high burden of RSV infections in older adults and those with chronic conditions, and the need for preventive strategies.

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.

Clinical impact of accepting or rejecting a recommendation from a clinical decision support system-assisted antibiotic stewardship program.

Background: Outcomes associated with physician responses to recommendations from an antimicrobial stewardship program (ASP) at an individual patient level have not yet been assessed. We aimed to compare clinical characteristics and mortality risk among patients for whom recommendations from an ASP were accepted or refused. Methods: A prospective cohort study was performed with hospitalized adults who received intravenous or oral antimicrobials at a 677-bed academic centre in Canada in 2014-2017. We included patients with an alert produced by a clinical decision support system (CDSS) for whom a recommendation was made by the pharmacist to the attending physician. The outcome was 90-day in-hospital all-cause mortality. Results: We identified 3,197 recommendations throughout the study period, of which 2,885 (90.2%) were accepted. The median length of antimicrobial treatment was significantly shorter when a recommendation was accepted (0.26 versus 1.78 d; p < 0.001). Refusal of a recommendation was not associated with mortality (odds ratio 1.32; 95% confidence interval, 0.93 to 1.89; p = 0.12). The independent risk factors associated with in-hospital mortality were age, Charlson Comorbidity Index score, admission to a critical care unit, duration between admission and recommendation, and issuance of a recommendation on a carbapenem. Conclusions: The duration of antimicrobial treatment was significantly shorter when a recommendation originating from a CDSS-assisted ASP program was accepted. Future prospective studies including potential residual confounding variables, such as the source of infection or physiological derangement, might help in understanding whether CDSS-assisted ASP will have a direct impact on patient mortality.

Historique: Les résultats liés aux réponses des médecins aux recommandations du programme de gestion antimicrobienne (PGA) n'ont pas encore été évalués à l'égard de chaque patient. Les chercheurs ont visé à comparer les caractéristiques cliniques et le risque de mortalité chez les patients dont les recommandations provenant d'une PGA ont été acceptées ou refusées. Méthodologie: Les chercheurs ont procédé à une étude de cohorte prospective auprès d'adultes hospitalisés qui avaient reçu des antimicrobiens par voie intraveineuse ou orale à un centre universitaire de 667 lits composé de deux établissements du Canada entre 2014 et 2017. Ils ont inclus les patients pour qui s'était déclenchée une alerte produite par un système d'aide à la décision clinique (SADC) et pour qui le pharmacien avait fait une recommandation au médecin traitant. Le résultat était la mortalité toutes causes confondues après un séjour hospitalier de 90 jours. Résultats: Les chercheurs ont extrait 3 197 recommandations tout au long de l'étude, dont 2 885 (90,2 %) ont été acceptées. La durée médiane du traitement antimicrobien était considérablement plus courte lorsqu'une recommandation était acceptée (0,26 par rapport à 1,78 jour; p < 0,001). Le refus d'une recommandation n'était pas associé à la mortalité (rapport de cotes de 1,32; IC de 95 %, 0,93 à 1,89; p = 0,12). Les facteurs de risque indépendants associés à la mortalité en milieu hospitalier étaient l'âge, l'indice de Charlson, l'admission dans une unité de soins intensifs, la période entre l'admission et la recommandation, et la formulation d'une recommandation sur un carbapénem. Conclusion: La durée du traitement antimicrobien était beaucoup plus courte lorsque la recommandation d'un PGA assisté par un SADC était acceptée. De futures études prospectives incluant de potentielles variables confusionnelles résiduelles, telles que la source de l'infection ou le dérangement physiologique, pourraient contribuer à établir si un PGA assisté par un SADC aura des conséquences directes sur la mortalité des patients.

Epidemiology of varicella among immigrants and non-immigrants in Quebec, Canada, before and after the introduction of childhood varicella vaccination: a retrospective cohort study.

BACKGROUND: Many immigrants are susceptible to varicella on arrival to Canada because of different transmission dynamics in their countries of origin and scarcity of vaccination. Universal childhood vaccination programmes decrease varicella incidence rates through herd immunity, but the accumulating number of susceptible adult immigrants could remain at risk for severe varicella. Our aim was to describe the epidemiology of varicella among immigrants and non-immigrants before and after childhood varicella vaccination. METHODS: We did a population-based, retrospective cohort study of all varicella cases in Quebec, Canada, diagnosed between 1996 and 2014 in administrative health databases linked to immigration data. Cases of varicella met diagnostic codes in the International Classification of Diseases, Ninth and Tenth Revision Canadian modifications. Cases with a co-occurring zoster diagnostic code and immigrants from Australia, New Zealand, the USA, and western European countries were excluded. Vaccination periods included pre-vaccination (1996-98), private vaccination (1999-2005), and public vaccination (2006-14). Incidence rate and comparative rate ratios were estimated using census data. FINDINGS: A total of 231 339 varicella cases diagnosed between Jan 1, 1996, and Dec 31, 2014, were linked to 1 115 696 immigrants who arrived between Jan 1, 1980, and Dec 31, 2014. 1444 herpes zoster cases and 1276 immigrants from Australia, western Europe, New Zealand, and the USA were excluded. Among 228 619 varicella cases, 13 315 (5·8%) occurred in immigrants. In pre-vaccination versus public vaccination periods, varicella incidence declined in immigrants by 87% (95% CI 86·6-87·9; 324·3 cases per 100 000 person-years to 40·9 cases per 100 000 person-years) and in non-immigrants by 93% (92·4-92·7; 484 cases per 100 000 person-years to 36 cases per 100 000 person-years). Mean age at diagnosis increased in both groups (15·1 vs 19·4 years in immigrants and 8·4 vs 12·0 years in non-immigrants). In the public vaccination period, immigrants younger than 50 years had higher varicella rates than non-immigrants, with relative risk ranging from 1·53 (95% CI 1·37-1·72) to 4·64 (3·90-5·53) with the highest risk in adolescents and young adults, and people from Latin America and the Caribbean (age-specific incidence rate ratio [aIRR]I-NI pre-vaccination 2·19 and post-vaccination aIRRI-NI6·07) and south Asia (aIRRI-NI pre-vaccination 3·41 and aIRRI-NI post-vaccination 4·46) and in childbearing women (15-40 years; IRRI-NI 2·48). INTERPRETATION: Immigrant adolescents, young adults, and women of childbearing age had higher age-standardised rates of varicella than non-immigrants, with increasing disparities following vaccine introduction. Immigrants younger than 50 years of age would benefit from targeted vaccination upon arrival to host countries. FUNDING: The Canadian Institutes of Health Research and The Department of Medicine, Jewish General Hospital, Montreal, QC, Canada.

Is Antimicrobial Dosing Adjustment Associated with Better Outcomes in Patients with Severe Obesity and Bloodstream Infections? An Exploratory Study.

The impact of adjusted treatment on clinical outcomes in patients with severe obesity is unclear. This study included adults with severe obesity admitted for bloodstream infections between 2005 and 2015. The patients were grouped according to the percentage of the appropriateness of the dosage of their antimicrobial treatment: 80-100% = good, 20-79% = moderate, and 0-19% = poor. The association between antimicrobial adjustment and a composite of unfavourable outcomes [intensive care unit stay ≥72 h, duration of sepsis >3 days, length of stay ≥7 days or all-cause 30-day mortality] was assessed using logistic regression. Of 110 included episodes, the adjustment was rated good in 47 (43%) episodes, moderate in 31 (28%), and poor in 32 (29%). Older age, Pitt bacteremia score ≥2, sepsis on day 1, and infection site were independent risk factors for unfavourable outcomes. The level of appropriateness was not associated with unfavourable outcomes. The number of antimicrobials, consultation with an infectious disease specialist, blood urea nitrogen 7-10.9 mmol/L, and hemodialysis were significantly associated with adjusted antimicrobial dosing. While the severity of the infection had a substantial impact on the measured outcomes, we did not find an association between dosing optimization and better outcomes.

External validation of clinical prediction rules for complications and mortality following Clostridioides difficile infection.

BACKGROUND: Several clinical prediction rules (CPRs) for complications and mortality of Clostridioides difficile infection (CDI) have been developed but only a few have gone through external validation, and none is widely recommended in clinical practice. METHODS: CPRs were identified through a systematic review. We included studies that predicted severe or complicated CDI (cCDI) and mortality, reported at least an internal validation step, and for which data were available with minimal modifications. Data from a multicenter prospective cohort of 1380 adults with confirmed CDI were used for external validation. In this cohort, cCDI occurred in 8% of the patients and 30-day all-cause mortality occurred in 12%. The performance of each tool was assessed using individual outcomes, with the same cut-offs and standard parameters. RESULTS: Seven CPRs were assessed. Three predictive scores for cCDI showed low sensitivity (25-61%) and positive predictive value (PPV; 9-31%), but moderate specificity (54-90%) and negative predictive value (NPV; 82-95%). One model [using age, white blood cell count (WBC), narcotic use, antacids use, and creatinine ratio > 1.5× the normal level as covariates] showed a probability of 25% of cCDI at the optimal cut-off point with 36% sensitivity and 84% specificity. Two scores for mortality had low sensitivity (4-55%) and PPV (25-31%), and moderate specificity (71-78%) and NPV (87-92%). One predictive model for 30-day all-cause mortality [Charlson comorbidity index, WBC, blood urea nitrogen (BUN), diagnosis in ICU, and delirium] showed an AUC-ROC of 0.74. All other CPRs showed lower AUC values (0.63-0.69). Errors in calibration ranged from 12%- 27%. CONCLUSIONS: Included CPRs showed moderate performance for clinical use in a large validation cohort with a majority of patients infected with ribotype 027 strains and a low rate of cCDI and mortality. These data show that better CPRs need to be developed and validated.

Prevalence of antibiotic-resistant organisms in Canadian Hospitals. Comparison of point-prevalence survey results from 2010, 2012, and 2016.

OBJECTIVE: Point-prevalence surveys for infection or colonization with methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae (CREs), and for Clostridium difficile infection (CDI) were conducted in Canadian hospitals in 2010 and 2012 to better understanding changes in the epidemiology of antimicrobial-resistant organisms (AROs), which is crucial for public health and care management. METHODS: A third survey of the same AROs in adult inpatients in Canadian hospitals with ≥50 beds was performed in February 2016. Data on participating hospitals and patient cases were obtained using standard criteria and case definitions. Associations between ARO prevalence and institutional characteristics were assessed using logistic regression models. RESULTS: In total, 160 hospitals from 9 of the 10 provinces with 35,018 adult inpatients participated in the survey. Median prevalence per 100 inpatients was 4.1 for MRSA, 0.8 for VRE, 1.1 for CDI, 0.8 for ESBLs, and 0 for CREs. No significant change occurred compared to 2012. CREs were reported from 24 hospitals (15%) in 2016 compared to 10 hospitals (7%) in 2012. Routine universal or targeted admission screening for VRE decreased from 94% in 2010 to 74% in 2016. Targeted screening for MRSA on admission was associated with a lower prevalence of MRSA infection. Large hospitals (>500 beds) had higher prevalences of CDI. CONCLUSION: This survey provides national prevalence rates for AROs in Canadian hospitals. Changes in infection control and prevention policies might lead to changes in the epidemiology of AROs and our capacity to detect them.

Risk factors for recurrence, complications and mortality in Clostridium difficile infection: a systematic review.

BACKGROUND: Clostridium difficile infection (CDI) can lead to complications, recurrence, and death. Numerous studies have assessed risk factors for these unfavourable outcomes, but systematic reviews or meta-analyses published so far were limited in scope or in quality. METHODS: A systematic review was completed according to PRISMA guidelines. An electronic search in five databases was performed. Studies published until October 2013 were included if risk factors for at least one CDI outcome were assessed with multivariate analyses. RESULTS: 68 studies were included: 24 assessed risk factors for recurrence, 18 for complicated CDI, 8 for treatment failure, and 30 for mortality. Most studies accounted for mortality in the definition of complicated CDI. Important variables were inconsistently reported, such as previous episodes and use of antibiotics. Substantial heterogeneity and methodological limitations were noted, mainly in the sample size, the definition of the outcomes and periods of follow-up, precluding a meta-analysis. Older age, use of antibiotics after diagnosis, use of proton pump inhibitors, and strain type were the most frequent risk factors for recurrence. Older age, leucocytosis, renal failure and co-morbidities were frequent risk factors for complicated CDI. When considered alone, mortality was associated with age, co-morbidities, hypo-albuminemia, leucocytosis, acute renal failure, and infection with ribotype 027. CONCLUSION: Laboratory parameters currently used in European and American guidelines to define patients at risk of a complicated CDI are adequate. Strategies for the management of CDI should be tailored according to the age of the patient, biological markers of severity, and underlying co-morbidities.

Evolution of the global burden of viral infections from unsafe medical injections, 2000-2010.

BACKGROUND: In 2000, the World Health Organization estimated that, in developing and transitional countries, unsafe injections accounted for respectively 5%, 32% and 40% of new infections with HIV, hepatitis B virus (HBV) and hepatitis C virus (HCV). Safe injection campaigns were organized worldwide. The present study sought to measure the progress in reducing the transmission of these viruses through unsafe injections over the subsequent decade. METHODS: A mass action model was updated, to recalculate the number of injection-related HIV, HCV and HBV infections acquired in 2000 and provide estimates for 2010. Data about the annual number of unsafe injections were updated. HIV prevalence in various regions in 2000 and 2010 were calculated from UNAIDS data. The ratio of HIV prevalence in healthcare settings compared to the general population was estimated from a literature review. Improved regional estimates of the prevalence of HCV seropositivity, HBsAg and HBeAg antigenemia were used for 2000 and 2010. For HIV and HCV, revised estimates of the probability of transmission per episode of unsafe injection were used, with low and high values allowing sensitivity analyses. RESULTS: Despite a 13% population growth, there was a reduction of respectively 87% and 83% in the absolute numbers of HIV and HCV infections transmitted through injections. For HBV, the reduction was more marked (91%) due to the additional impact of vaccination. While injections-related cases had accounted for 4.6%-9.1% of newly acquired HIV infections in 2000, this proportion decreased to 0.7%-1.3% in 2010, when unsafe injections caused between 16,939 and 33,877 HIV infections, between 157,592 and 315,120 HCV infections, and 1,679,745 HBV infections. CONCLUSION: From 2000 to 2010, substantial progress was made in reducing the burden of HIV, HCV and HBV infections transmitted through injections. In some regions, their elimination might become a reasonable public health goal.