Infectious diseases, comorbidities and outcomes in hospitalized people who inject drugs (PWID) infections in persons who inject drugs.

Injection drug use poses a public health challenge. Clinical experience indicates that people who inject drugs (PWID) are hospitalized frequently for infectious diseases, but little is known about outcomes when admitted. Charts were identified from local hospitals between 2013-2018 using consultation lists and hospital record searches. Included individuals injected drugs in the past six months and presented with infection. Charts were accessed using the hospital information system, undergoing primary and secondary reviews using Research Electronic Data Capture (REDCap). The Wilcoxon rank-sum test was used for comparisons between outcome categories. Categorical data were summarized as count and frequency, and compared using Fisher's exact test. Of 240 individuals, 33% were admitted to the intensive care unit, 36% underwent surgery, 12% left against medical advice (AMA), and 9% died. Infectious diagnoses included bacteremia (31%), abscess (29%), endocarditis (29%), cellulitis (20%), sepsis (10%), osteomyelitis (9%), septic arthritis (8%), pneumonia (7%), discitis (2%), meningitis/encephalitis (2%), or other (7%). Sixty-six percent had stable housing and 60% had a family physician. Fifty-four percent of patient-initiated discharges were seen in the emergency department within 30 days and 29% were readmitted. PWID are at risk for infections. Understanding their healthcare trajectory is essential to improve their care.

Secondary Analysis of a Systematic Review: Are Antifungal Noninferiority Trials at Risk of Eroding Effectiveness Because of Biocreep?

Noninferiority randomized controlled trial (RCT) effectiveness may erode when results favor the active control over time and when a decreasingly effective control arm is used in serial trials. We analyzed 32 antifungal noninferiority RCTs (NI-RCTs) for these scenarios in this secondary analysis of a systematic review. Our exploratory analysis suggests that the erosion risk in the effectiveness of antifungal noninferiority trials is uncommon. Findings are limited by small sample size and overall risk of bias.

Methodological and reporting quality of non-inferiority randomized controlled trials comparing antifungal therapies: a systematic review.

BACKGROUND: Detailed reporting is essential in non-inferiority randomized controlled trials (NI-RCTs) to assess evidence quality, as these trials inform standards of care. OBJECTIVES: The primary objective was to evaluate the methodological and reporting quality of antifungal NI-RCTs. DATA SOURCES: Medline, EMBASE, the Cochrane CENTRAL and the United States Federal Drug Administration (FDA) drugs database were searched to 9 September 2020. STUDY ELIGIBILITY CRITERIA: NI-RCTs differing by antifungal formulation, type, dose, administration and/or duration were included. Articles were independently assessed in duplicate using quality indicators developed by the Consolidated Standards of Reporting Trials (CONSORT) group. PARTICIPANTS: Patients enrolled in antifungal trials for prophylactic and therapeutic use. METHODS: The Cochrane RoB 2.0 tool was used to assess risk of bias. Descriptive statistics were used; all statistical tests were two sided. RESULTS: Of 32 included studies, 22 (68.7%) did not justify the NIM. Handling of missing data was not described in 20 (62.5%). Intention-to-treat (ITT) and per-protocol (PP) analyses were both reported in 12/32 (37.5%) studies. Eleven of 32 studies (34.3%) reported potentially misleading conclusions. Industry-financed studies were more likely to report only the ITT analysis (n = 14/27, 51.9%). Methodological and reporting quality was unaffected by publication year; risk of bias from missing data changed over time. Overall risk of bias across included studies was moderate to high, with high risk in randomization process (n = 8/32, 25%), missing outcome data (n = 5/32, 15.6%), and selection of reported result (n = 9/32, 28.1%). CONCLUSIONS: Justification of the non-inferiority margin, reporting of ITT and PP analyses, missing data handling description, and ensuring conclusions are consistent with reported data is necessary to improve CONSORT adherence. Small sample size and overall risk of bias are study limitations. (Systematic Review Registration Number PROSPERO CRD42020219497).

Confidence interval of risk difference by different statistical methods and its impact on the study conclusion in antibiotic non-inferiority trials.

BACKGROUND: Numerous statistical methods can be used to calculate the confidence interval (CI) of risk differences. There is consensus in previous literature that the Wald method should be discouraged. We compared five statistical methods for estimating the CI of risk difference in terms of CI width and study conclusion in antibiotic non-inferiority trials. METHODS: In a secondary analysis of a systematic review, we included non-inferiority trials that compared different antibiotic regimens, reported risk differences for the primary outcome, and described the number of successes and/or failures as well as patients in each arm. For each study, we re-calculated the risk difference CI using the Wald, Agresti-Caffo, Newcombe, Miettinen-Nurminen, and skewness-corrected asymptotic score (SCAS) methods. The CIs by different statistical methods were compared in terms of CI width and conclusion on non-inferiority. A wider CI was considered to be more conservative. RESULTS: The analysis included 224 comparisons from 213 studies. The statistical method used to calculate CI was not reported in 134 (59.8%) cases. The median (interquartile range IQR) for CI width by Wald, Agresti-Caffo, Newcombe, Miettinen-Nurminen, and SCAS methods was 13.0% (10.8%, 17.4%), 13.3% (10.9%, 18.5%), 13.6% (11.1%, 18.9%), 13.6% (11.1% and 19.0%), and 13.4% (11.1%, 18.9%), respectively. In 216 comparisons that reported a non-inferiority margin, the conclusion on non-inferiority was the same across the five statistical methods in 211 (97.7%) cases. The differences in CI width were more in trials with a sample size of 100 or less in each group and treatment success rate above 90%. Of the 18 trials in this subgroup with a specified non-inferiority margin, non-inferiority was shown in 17 (94.4%), 16 (88.9%), 14 (77.8%), 14 (77.8%), and 15 (83.3%) cases based on CI by Wald, Agresti-Caffo, Newcombe, Miettinen-Nurminen, and SCAS methods, respectively. CONCLUSIONS: The statistical method used to calculate CI was not reported in the majority of antibiotic non-inferiority trials. Different statistical methods for CI resulted in different conclusions on non-inferiority in 2.3% cases. The differences in CI widths were highest in trials with a sample size of 100 or less in each group and a treatment success rate above 90%. TRIAL REGISTRATION: PROSPERO CRD42020165040 . April 28, 2020.

Cefazolin versus cloxacillin as definitive antibiotic therapy for methicillin-susceptible Staphylococcus aureus spinal epidural abscess: a retrospective cohort study.

OBJECTIVES: We compared the effectiveness of cefazolin and cloxacillin as definitive antibiotic therapy for methicillin-susceptible Staphylococcus aureus (MSSA) spinal epidural abscess (SEA). METHODS: This retrospective cohort study included patients with MSSA SEA from two academic hospitals in Hamilton, Ontario, Canada, between 2014 and 2020. Patients treated with cefazolin were compared to those treated with cloxacillin. Co-primary outcomes included 90-day mortality, antibiotic failure, adverse reactions and recurrence. Inverse probability of treatment weighting using propensity scores was used to balance important prognostic factors and to estimate an adjusted risk difference. RESULTS: Of 98 patients with MSSA SEA, 50 and 48 patients were treated with cefazolin and cloxacillin, respectively. Mortality at 90 days was 8% and 13% in the cefazolin and cloxacillin groups, respectively (P = 0.52). The antibiotic failure rate was 12% and 19% in the cefazolin and cloxacillin groups, respectively (P = 0.41). The serious adverse reactions rate was 0% and 4% in the cefazolin and cloxacillin groups, respectively (P = 0.24). The recurrence rate was 2% and 8% in the cefazolin and cloxacillin groups, respectively (P = 0.20). The adjusted risk difference for mortality at 90 days was -1% [95% confidence interval (CI) -10% to 8%] favouring cefazolin. The adjusted risk differences for antibiotic failure, adverse reactions and recurrence were 1% (95% CI -12% to 14%), -5% (95% CI -11% to 2%) and -18% (-36% to -1%) respectively. CONCLUSION: Cefazolin is likely as effective as an antistaphylococcal penicillin and may be considered as a first-line treatment for MSSA SEA.

Intention-to-treat analysis may be more conservative than per protocol analysis in antibiotic non-inferiority trials: a systematic review.

BACKGROUND: In non-inferiority trials, there is a concern that intention-to-treat (ITT) analysis, by including participants who did not receive the planned interventions, may bias towards making the treatment and control arms look similar and lead to mistaken claims of non-inferiority. In contrast, per protocol (PP) analysis is viewed as less likely to make this mistake and therefore preferable in non-inferiority trials. In a systematic review of antibiotic non-inferiority trials, we compared ITT and PP analyses to determine which analysis was more conservative. METHODS: In a secondary analysis of a systematic review, we included non-inferiority trials that compared different antibiotic regimens, used absolute risk reduction (ARR) as the main outcome and reported both ITT and PP analyses. All estimates and confidence intervals (CIs) were oriented so that a negative ARR favored the control arm, and a positive ARR favored the treatment arm. We compared ITT to PP analyses results. The more conservative analysis between ITT and PP analyses was defined as the one having a more negative lower CI limit. RESULTS: The analysis included 164 comparisons from 154 studies. In terms of the ARR, ITT analysis yielded the more conservative point estimate and lower CI limit in 83 (50.6%) and 92 (56.1%) comparisons respectively. The lower CI limits in ITT analysis favored the control arm more than in PP analysis (median of - 7.5% vs. -6.9%, p = 0.0402). CIs were slightly wider in ITT analyses than in PP analyses (median of 13.3% vs. 12.4%, p < 0.0001). The median success rate was 89% (interquartile range IQR 82 to 93%) in the PP population and 44% (IQR 23 to 60%) in the patients who were included in the ITT population but excluded from the PP population (p < 0.0001). CONCLUSIONS: Contrary to common belief, ITT analysis was more conservative than PP analysis in the majority of antibiotic non-inferiority trials. The lower treatment success rate in the ITT analysis led to a larger variance and wider CI, resulting in a more conservative lower CI limit. ITT analysis should be mandatory and considered as either the primary or co-primary analysis for non-inferiority trials. TRIAL REGISTRATION: PROSPERO registration number CRD42020165040 .

Methodological and Reporting Quality of Noninferiority Randomized Controlled Trials Comparing Antibiotic Therapies: A Systematic Review.

BACKGROUND: Antibiotic noninferiority randomized controlled trials (RCTs) are used for approval of new antibiotics and making changes to antibiotic prescribing in clinical practice. We conducted a systematic review to assess the methodological and reporting quality of antibiotic noninferiority RCTs. METHODS: We searched MEDLINE, Embase, the Cochrane Database of Systematic Reviews, and the Food and Drug Administration drug database from inception until November 22, 2019, for noninferiority RCTs comparing different systemic antibiotic therapies. Comparisons between antibiotic types, doses, administration routes, or durations were included. Methodological and reporting quality indicators were based on the Consolidated Standards of Reporting Trials reporting guidelines. Two independent reviewers extracted the data. RESULTS: The systematic review included 227 studies. Of these, 135 (59.5%) studies were supported by pharmaceutical industry. Only 83 (36.6%) studies provided a justification for the noninferiority margin. Reporting of both intention-to-treat (ITT) and per-protocol (PP) analyses were done in 165 (72.7%) studies. The conclusion was misleading in 34 (15.0%) studies. The studies funded by pharmaceutical industry were less likely to be stopped early because of logistical reasons (3.0% vs 19.1%; odds ratio [OR] = 0.13; 95% confidence interval [CI], .04-.37) and to show inconclusive results (11.1% vs 42.9%; OR = 0.17; 95% CI, .08-.33). The quality of studies decreased over time with respect to blinding, early stopping, reporting of ITT with PP analysis, and having misleading conclusions. CONCLUSIONS: There is room for improvement in the methodology and reporting of antibiotic noninferiority trials. Quality can be improved across the entire spectrum from investigators, funding agencies, as well as during the peer-review process.There is room for improvement in the methodology and reporting of antibiotic noninferiority trials including justification of noninferiority margin, reporting of intention-to-treat analysis with per-protocol analysis, and having conclusions that are concordant with study results.Clinical Trials Registration PROSPERO registration number CRD42020165040.

Novel Antibiotics May Be Noninferior but Are They Becoming Less Effective?: a Systematic Review.

Novel antibiotics approved by noninferiority trials may become less effective over time in two scenarios: (i) the treatment effect in studies of novel antibiotics may be consistently worse than studies of older antibiotics; (ii) when a decreasingly effective control arm is used in a series of noninferiority trials. Our systematic review of 175 noninferiority antibiotic trials found these scenarios to be rare.

Listeria pericarditis in a lymphoma patient: Case report and literature review.

We present a case of pericarditis with pericardial effusion secondary to Listeria monocytogenes. A 56-year-old man presented with signs of acute pericarditis, but with prior chronic lymphocytic leukemia treated with stem cell transplantation, chronic graft-versus-host disease, and a recent diagnosis of untreated diffuse large B-cell lymphoma. He developed cardiac tamponade requiring pericardiocentesis. Blood and pericardial cultures grew Listeria monocytogenes. He responded to ampicillin but later died from gram-negative sepsis. A systematic review found 10 other published English-language cases of pericarditis caused by Listeria. The most common risk factors were cirrhosis and malignancy. Only three patients survived both the listeriosis and their underlying infections. Listeria monocytogenes is a rare and often fatal cause of pericarditis, typically occurring in immunocompromised patients. Cultures showing gram-positive bacilli in the context of pericarditis in an immunocompromised patient should prompt consideration of this rare cause.

Les auteurs présentent un cas de péricardite avec effusion secondaire au Listeria monocytogenes. Un homme de 56 ans a consulté à cause de signes de péricardite aiguë. Il souffrait déjà d'une leucémie lymphoïde chronique traitée par une greffe de cellules souches et d'une réaction chronique du greffon contre l'hôte et avait récemment reçu un diagnostic de lymphome diffus à grandes cellules B non traité. Il a développé une tamponnade cardiaque exigeant une péricardiocentèse. Les cultures sanguine et péricardique ont révélé la présence de Listeria monocytogenes. Le patient a répondu à l'ampicilline, mais a fini par mourir d'un sepsis à Gram négatif. Une analyse systématique a révélé dix autres cas de péricardite causés par la Listeria dans des publications en langue anglaise. La cirrhose et les tumeurs en étaient les principaux facteurs de risque. Seulement trois patients ont survécu à la fois à la listériose et à ses infections sous-jacentes. Le Listeria monocytogenes est une cause de péricardite rare et souvent fatale, qui se déclare généralement chez des hôtes immunodéprimés. Des cultures révélant des bacilles à Gram positif dans le contexte d'une péricardite chez un hôte immunodéprimé doivent inciter à envisager cette cause rare.

Factors Affecting Pre-Travel Health Seeking Behaviour and Adherence to Pre-Travel Health Advice: A Systematic Review.

BACKGROUND: Recent years have seen unprecedented growth in international travel. Travellers are at high risk for acquiring infections while abroad and potentially bringing these infections back to their home country. There are many ways to mitigate this risk by seeking pre-travel advice (PTA), including receiving recommended vaccinations and chemoprophylaxis, however many travellers do not seek or adhere to PTA. We conducted a systematic review to further understand PTA-seeking behaviour with an ultimate aim to implement interventions that improve adherence to PTA and reduce morbidity and mortality in travellers. METHODS: We conducted a systematic review of published medical literature selecting studies that examined reasons for not seeking PTA and non-adherence to PTA over the last ten years. 4484 articles were screened of which 56 studies met our search criteria after full text review. RESULTS: The major reason for not seeking or non-adherence to PTA was perceived low risk of infection while travelling. Side effects played a significant role for lack of adherence specific to malaria prophylaxis. CONCLUSIONS: These data may help clinicians and public health providers to better understand reasons for non-adherence to PTA and target interventions to improve travellers understanding of potential and modifiable risks. Additionally, we discuss specific recommendations to increase public health education that may enable travellers to seek PTA.

The use of air travel data for predicting dengue importation to China: A modelling study.

BACKGROUND: Dengue virus importation from abroad is still the main driver of dengue incidence in China. Using global flight data to model importation may improve our understanding and prediction of dengue virus importation and onward transmission. METHODS: A retrospective analysis was performed of surveillance cases of dengue infections imported to China and volume of air traffic to China for the years 2005 through 2014, inclusive. The data were aggregated by year, destination province, and source country. Descriptive statistics were calculated, and a random effects negative binomial model was created to predict the number of imported cases based on the volume of travelers from dengue-endemic countries. RESULTS: There were 1,822 cases of imported dengue infections over the study period. Most imported cases are from a small number of high-incidence countries with a large volume of travel to China, most notably Myanmar (22% of cases). The number of imported cases of dengue infections increased by 5.9% for every 10% increase in travel volume from dengue-endemic countries. CONCLUSION: Patterns of air travel have a measurable impact on the importation of dengue to China. Modelling dengue importation risk may be a useful strategy to direct public health surveillance and interventions.

Seasonal and interannual risks of dengue introduction from South-East Asia into China, 2005-2015.

Due to worldwide increased human mobility, air-transportation data and mathematical models have been widely used to measure risks of global dispersal of pathogens. However, the seasonal and interannual risks of pathogens importation and onward transmission from endemic countries have rarely been quantified and validated. We constructed a modelling framework, integrating air travel, epidemiological, demographical, entomological and meteorological data, to measure the seasonal probability of dengue introduction from endemic countries. This framework has been applied retrospectively to elucidate spatiotemporal patterns and increasing seasonal risk of dengue importation from South-East Asia into China via air travel in multiple populations, Chinese travelers and local residents, over a decade of 2005-15. We found that the volume of airline travelers from South-East Asia into China has quadrupled from 2005 to 2015 with Chinese travelers increased rapidly. Following the growth of air traffic, the probability of dengue importation from South-East Asia into China has increased dramatically from 2005 to 2015. This study also revealed seasonal asymmetries of transmission routes: Sri Lanka and Maldives have emerged as origins; neglected cities at central and coastal China have been increasingly vulnerable to dengue importation and onward transmission. Compared to the monthly occurrence of dengue reported in China, our model performed robustly for importation and onward transmission risk estimates. The approach and evidence could facilitate to understand and mitigate the changing seasonal threat of arbovirus from endemic regions.

Human Mobility and the Global Spread of Infectious Diseases: A Focus on Air Travel.

Greater human mobility, largely driven by air travel, is leading to an increase in the frequency and reach of infectious disease epidemics. Air travel can rapidly connect any two points on the planet, and this has the potential to cause swift and broad dissemination of emerging and re-emerging infectious diseases that may pose a threat to global health security. Investments to strengthen surveillance, build robust early-warning systems, improve predictive models, and coordinate public health responses may help to prevent, detect, and respond to new infectious disease epidemics.

Maternal near miss and mortality due to postpartum infection: a cross-sectional analysis from Rwanda.

BACKGROUND: The objective of this study is to evaluate 'near miss' and mortality in women with postpartum infections. METHODS: We performed a retrospective review of all patients referred to the University Teaching Hospital of Kigali (CHUK) between January 2012 and December 2013. We identified 117 patients with postpartum infections. Demographic data, length of admission, location of referral, initial surgery and subsequent treatment modalities including antibiotic administration and secondary surgery were recorded. The primary outcome of interest was a composite of maternal mortality and "near miss" defined as more than one laparotomy with/without hysterectomy and prolonged hospitalization. RESULTS: Diagnoses at CHUK were: pelvic peritonitis (56 %), deep surgical site infection including fasciitis (17 %), and endometritis (15 %). The primary procedures performed prior to transfer were: cesarean section (81 %), septic abortion management (12 %), and vaginal delivery (7 %). Antibiotics were initiated prior to transfer in 66 % of women. Surgery was required in 73 % of patients. Hysterectomies were performed in 22 % of patients. Maternal death occurred in 5 % of the patient population. The primary outcome of severe maternal morbidity and mortality occurred in 90 patients (77 %). CONCLUSION: Peritonitis-primarily as a result of cesarean deliveries-is associated with significant morbidity and mortality in our population.