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A letter to the editor and a response by Duminda N. Wijeysundera, W. Scott Beattie, Peter C. Austin, Janet E. Hux and Andreas Laupacis to letters about their article "Outcomes and Processes of Care Related to Preoperative Medical Consultation" in a 2010 issue are presented.

A letter to the editor is presented in response to the article "Clostridium difficile Infection" in the April 16, 2015 issue.

Background Tricuspid valve endocarditis caused by Group B streptococcus is a rare clinical entity with poor prognosis and has been previously reported following gynecologic procedures. Case summary We report a case of an 18-year-old female diagnosed with Group B streptococcus tricuspid valve endocarditis with septic emboli following an elective therapeutic abortion. After six weeks of treatment with ceftriaxone, she returned with recurrent symptoms and was found to have embolized a sizable vegetation to the pulmonary artery with probable lung infarction. She underwent surgical embolectomy and was treated with antibiotics and anticoagulation and was subsequently discharged in stable condition. Conclusion Group B streptococcus endocarditis is a serious complication of gynecologic procedures. The role of preoperative antibiotics, postoperative clinical suspicion of endocarditis based on respiratory symptoms and a multidisciplinary approach may lead to enhanced patient outcomes. [ABSTRACT FROM AUTHOR]

Background: International COVID-19 guidelines recommend thromboprophylaxis for non-critically ill inpatients to prevent thrombotic complications. It is still debated whether full-dose thromboprophylaxis reduces all-cause mortality. The main aim of this updated systematic review and meta-analysis is to evaluate the effect of full-dose heparin-based thromboprophylaxis on survival in hospitalized non-critically ill COVID-19 patients. Methods: A systematic review was performed across Pubmed/Medline, EMBASE, Cochrane Central Register of clinical trials, Clinicaltrials.gov, and medRxiv.org from inception to November 2022. We conducted a meta-analysis of randomized clinical trials (RCTs) comparing full-dose heparin-based anticoagulation to prophylactic or intermediate dose anticoagulation or standard treatment in hospitalized non-critically ill COVID-19 patients. The risk of bias was assessed using the Cochrane risk-of-bias tool for randomized trials and Grading of Recommendations Assessment, Development and Evaluation was applied. The primary outcome was all-cause mortality at the longest follow-up available. Results: We identified 6 multicenter RCTs involving 3297 patients from 13 countries across 4 continents. The rate of all-cause mortality was 6.2% (103/1662) in the full-dose group vs 7.7% (126/1635) in the prophylactic or intermediate dose group (Risk Ratio [RR] = 0.76; 95% confidence interval [CI] = 0.59–0.98; P = 0.037). The probabilities of any mortality difference and of NNT ≤ 100 were estimated at 98.2% and 84.5%, respectively. The risk of bias was low for all included RCTs and the strength of the evidence was "moderate." Conclusion: Our meta-analysis of high-quality multicenter RCTs suggests that full-dose anticoagulation with heparin or low molecular weight heparin reduces all-cause mortality in hospitalized non-critically ill COVID-19 patients. Study registration: PROSPERO, review no. CRD42022348993. [ABSTRACT FROM AUTHOR]

Hydroxychloroquine (HCQ) was initially promoted as an oral therapy for early treatment of coronavirus disease 2019 (COVID‐19). Conventional meta‐analyses cannot fully address the heterogeneity of different designs and outcomes of randomized controlled trials (RCTs) assessing the efficacy of HCQ in outpatients with mild COVID‐19. We conducted a pooled analysis of individual participant data from RCTs that evaluated the effect of HCQ on hospitalization and viral load reduction in outpatients with confirmed COVID‐19. We evaluated the overall treatment group effect by log‐likelihood ratio test (−2LL) from a generalized linear mixed model to accommodate correlated longitudinal binary data. The analysis included data from 11 RCTs. The outcome of virological effect, assessed in 1560 participants (N = 795 HCQ, N = 765 control), did not differ significantly between the two treatment groups (−2LL = 7.66; p = 0.18) when adjusting for cohort, duration of symptoms, and comorbidities. The decline in polymerase chain reaction positive tests from day 1 to 7 was 42.0 and 41.6 percentage points in the HCQ and control groups, respectively. Among the 2037 participants evaluable for hospitalization (N = 1058 HCQ, N = 979 control), we found no significant differences in hospitalization rate between participants receiving HCQ and controls (odds ratio 0.995; 95% confidence interval 0.614–1.610; −2LL = 0.0; p = 0.98) when adjusting for cohort, duration of symptoms, and comorbidities. This individual participant data meta‐analysis of 11 HCQ trials that evaluated severe acute respiratory syndrome‐coronavirus 2 viral clearance and COVID‐19 hospitalization did not show a clinical benefit of HCQ. Our meta‐analysis provides evidence to support the interruption in the use of HCQ in mild COVID‐19 outpatients to reduce progression to severe disease. [ABSTRACT FROM AUTHOR]

Background Toxoplasmic encephalitis (TE) is an opportunistic infection of people with human immunodeficiency virus (HIV) or other causes of immunosuppression. Guideline-recommended treatments for TE are pyrimethamine and sulfadiazine (P-S) or pyrimethamine and clindamycin (P-C); however, a substantial price increase has limited access to pyrimethamine. Consequently, some centers have transitioned to trimethoprim-sulfamethoxazole (TMP-SMX), an inexpensive alternative treatment. We aimed to review the evidence on the efficacy and safety of pyrimethamine-containing therapies vs TMP-SMX. Methods We searched for and included randomized controlled trials (RCTs) and observational studies of TE treatments, regardless of HIV status. Data for each therapy were pooled by meta-analysis to assess the proportions of patients who experienced clinical and radiologic responses to treatment, all-cause mortality, and discontinuation due to toxicity. Sensitivity analyses limited to RCTs directly compared therapies. Results We identified 6 RCTs/dose-escalation studies and 26 single-arm/observational studies. Identified studies included only persons with HIV, and most predated modern antiretroviral treatment. Pooled proportions of clinical and radiologic response and mortality were not significantly different between TMP-SMX and pyrimethamine-containing regimens (P >.05). Treatment discontinuation due to toxicity was significantly lower in TMP-SMX (7.3%; 95% confidence interval [CI], 4.7–11.4; I2 = 0.0%) vs P-S (30.5%; 95% CI, 27.1–34.2; I2 = 0.0%; P <.01) or P-C (13.7%; 95% CI, 9.8–18.8; I2 = 32.0%; P =.031). These results were consistent in analyses restricted to RCT data. Conclusions TMP-SMX appears to be as effective and safer than pyrimethamine-containing regimens for TE. These findings support modern RCTs comparing TMP-SMX to pyrimethamine-based therapies and a revisiting of the guidelines. [ABSTRACT FROM AUTHOR]

Studies comparing shorter and longer antibiotic treatment durations are increasingly common. Randomized controlled trials (RCTs) are an ideal methodological approach to study antibiotic treatment durations; however, these trials can be logistically and financially challenging to conduct. In this narrative review, we sought to compare the strengths and limitations of observational study data with those of RCT data in evaluating antibiotic treatment durations. We used uncomplicated Gram-negative bacteraemia as an illustrative case example because several published RCTs and observational studies have been conducted in similar patient populations. We searched MEDLINE for articles comparing treatment durations for gram-negative bacteremia from inception to June 9th, 2022. We included studies reporting on all-cause mortality and/or relapse at day 28-30. Data comparing short- versus long-course therapy were pooled by Bayesian random effects meta-analyses to assess the odds ratios (OR) of all-cause mortality and relapse at 30 days, stratified by study design. Parameters were summarized with median and 95% highest-density credible intervals (CrI). Posterior probabilities of OR > 1.0 were estimated. Observational studies were further examined to determine if and how they addressed potential sources of bias. We identified 1671 unique records and included 10 studies (seven observational and three RCTs). With respect to 30-day mortality, the Bayesian posterior probability that a longer course of therapy was better (i.e. OR >1.0) was 42% in RCTs (OR, 0.94; 95% CrI, 0.51–1.68) and 91% in observational studies (OR, 1.25; 95% CrI, 0.88–1.73). No observational study fully addressed all potential sources of bias. On the basis of our findings, we discuss future directions for antibiotic treatment duration trials, including approaches to limit sources of bias in observation data and novel trial designs. [ABSTRACT FROM AUTHOR]

Like all fields of medicine, Infectious Diseases is rife with dogma that underpins much clinical practice. In this study, we discuss 2 specific examples of historical practice that have been overturned recently by numerous prospective studies: traditional durations of antimicrobial therapy and the necessity of intravenous (IV)-only therapy for specific infectious syndromes. These dogmas are based on uncontrolled case series from >50 years ago, amplified by the opinions of eminent experts. In contrast, more than 120 modern, randomized controlled trials have established that shorter durations of therapy are equally effective for many infections. Furthermore, 21 concordant randomized controlled trials have demonstrated that oral antibiotic therapy is at least as effective as IV-only therapy for osteomyelitis, bacteremia, and endocarditis. Nevertheless, practitioners in many clinical settings remain refractory to adopting these changes. It is time for Infectious Diseases to move beyond its history of eminent opinion-based medicine and truly into the era of evidenced-based medicine. [ABSTRACT FROM AUTHOR]

Randomized controlled trials (RCT) established the mortality reduction by tocilizumab (Actemra), baricitinib (Olumiant), and sarilumab (Kevzara) in hospitalized COVID-19 patients. However, uncertainty remains about which treatment performs best in patients receiving corticosteroids. To estimate probabilities of noninferiority between baricitinib and sarilumab compared to tocilizumab in patients treated with corticosteroids. PubMed, Embase, Cochrane Library, and MedRxiv. Eligible RCTs assigning hospitalized adults with COVID-19 treated with corticosteroids to tocilizumab or baricitinib or sarilumab versus standard of care or placebo (control). Reviewers independently abstracted published data and assessed study quality with the Risk of Bias 2 tool. Unpublished data, if required, were requested from authors of included studies. The outcome of interest was all-cause mortality at 28 days. Twenty-seven RCTs with 13 549 patients were included. Overall, the risk of bias was low. Bayesian pairwise meta-analyses were used to aggregate results of each treatment versus control. The average odds ratio for mortality was 0.78 (95% credible interval [CrI]: 0.65, 0.94) for tocilizumab; 0.78 (95% CrI: 0.56, 1.03) for baricitinib; and 0.91 (95% CrI: 0.60, 1.40) for sarilumab. The certainty of evidence (GRADE) ranged from moderate to low. Bayesian meta-regressions with multiple priors were used to estimate probabilities of noninferiority (margin of 13% greater effect by tocilizumab). Compared to tocilizumab, there were ≤94% and 90% probabilities of noninferiority with baricitinib and sarilumab, respectively. All but two studies included data with only indirect evidence for the comparison of interest. Among hospitalized COVID-19 treated with corticosteroids, there are high probabilities that both baricitinib and sarilumab are associated with similar mortality reductions in comparison to tocilizumab. [ABSTRACT FROM AUTHOR]

Staphylococcus aureus bloodstream (SAB) infection is a common and severe infectious disease, with a 90-day mortality of 15%–30%. Despite this, <3000 people have been randomized into clinical trials of treatments for SAB infection. The limited evidence base partly results from clinical trials for SAB infections being difficult to complete at scale using traditional clinical trial methods. Here we provide the rationale and framework for an adaptive platform trial applied to SAB infections. We detail the design features of the Staphylococcus aureus Network Adaptive Platform (SNAP) trial that will enable multiple questions to be answered as efficiently as possible. The SNAP trial commenced enrolling patients across multiple countries in 2022 with an estimated target sample size of 7000 participants. This approach may serve as an exemplar to increase efficiency of clinical trials for other infectious disease syndromes. [ABSTRACT FROM AUTHOR]

Background Based primarily on in vitro and animal models, with little data directly addressing patient outcomes, current guidelines recommend treating staphylococcal prosthetic valve endocarditis (PVE) with antibiotic combinations including gentamicin and rifampin. Here, we synthesize the clinical data on adjunctive rifampin and gentamicin in staphylococcal PVE. Methods We conducted a systematic review and meta-analysis of PubMed- and Cochrane-indexed studies reporting outcomes of staphylococcal PVE treated with adjunctive rifampin, gentamicin, both agents, or neither (ie, glycopeptide or β-lactam monotherapy). We recorded outcomes including mortality, relapsed infection, length of stay, nephrotoxicity, hepatotoxicity, and important drug–drug interactions (DDIs). Results Four relevant studies were identified. Two studies (n = 117) suggested that adding gentamicin to rifampin-containing regimens did not reduce clinical failure (odds ratio [OR], 0.98 [95% confidence interval {CI},.39–2.46]), and 2 studies (n = 201) suggested that adding rifampin to gentamicin-containing regimens did not reduce clinical failure (OR, 1.29 [95% CI,.71–2.33]). Neither gentamicin nor rifampin was associated with reduced infection relapse; 1 study found that rifampin treatment was associated with longer hospitalizations (mean, 31.3 vs 42.3 days; P <.001). Comparative safety outcomes were rarely reported, but 1 study found rifampin to be associated with hepatoxicity, nephrotoxicity, and DDIs, leading to treatment discontinuation in 31% of patients. Conclusions The existing clinical data do not suggest a benefit of either adjunctive gentamicin or rifampin in staphylococcal PVE. Given that other studies also suggest these agents add nephrotoxicity, hepatoxicity, and risk of DDIs without benefit in staphylococcal endovascular infections, we suggest that recommendations for gentamicin and rifampin in PVE be downgraded and primarily be used within the context of clinical trials. [ABSTRACT FROM AUTHOR]

In Staphylococcus aureus bacteremia, mortality rates in randomized controlled trials (RCTs) are consistently lower than observational studies. Stringent eligibility criteria and omission of early deaths in RCTs contribute to this mortality gap. Clinicians should acknowledge the possibility of a lower treatment effect when applying RCT results to bedside care. [ABSTRACT FROM AUTHOR]

• Styphylococcus aureus bacteremia (SAB) is common in low and middle-income countries (LMIC). • LMIC are poorly represented in SAB research. • In-hospital mortality for SAB is much higher in LMIC than in high-income countries. Staphylococcus aureus bacteremia (SAB) is a common infection worldwide. We compared SAB mortality in low- and middle-income countries (LMIC) versus high-income countries (HIC) in a meta-analysis. We searched MEDLINE, Embase, and Cochrane Database of Systematic Reviews from 1991-2021 and included observational, single-country studies on patients with positive blood cultures for S. aureus. The main outcome was the proportion of patients with SAB who died in the hospital. A generalized linear mixed random-effects model was used to pool estimates, and a meta-regression was used to adjust for study-level characteristics. A total of 332 studies involving 517,671 patients in 39 countries were included. No study was conducted in a low-income country. Only 33 (10%) studies were performed in middle-income countries (MIC), which described 6,216 patients. The pooled in-hospital mortality was 32.4% (95% confidence interval [CI] 27.2%-38.2%, T2 = 0.3063) in MIC and 22.3% (95% CI 20.1%-24.6%, T2 = 0.3257) in HIC. In a meta-regression model, MIC had higher in-hospital mortality (adjusted odds ratio 1.37, 95% CI 1.11-1.71; P = 0.0042) than HIC. In SAB studies, LMIC are poorly represented. In-hospital mortality was significantly higher in MIC than in HIC. Research should be conducted in LMIC to characterize differences in care processes driving the mortality gap. [ABSTRACT FROM AUTHOR]

Objectives: To determine whether angiotensin receptor blockers (ARBs) or angiotensin-converting enzyme (ACE) inhibitors are associated with improved outcomes in hospitalized patients with COVID-19 according to sex and to report sex-related differences in renin-angiotensin system (RAS) components.Design: Prospective observational cohort study comparing the effects of ARB or ACE inhibitors versus no ARBs or ACE inhibitors in males versus females. Severe acute respiratory syndrome coronavirus 2 downregulates ACE-2, potentially increasing angiotensin II (a pro-inflammatory vasoconstrictor). Sex-based differences in RAS dysregulation may explain sex-based differences in responses to ARBs because the ACE2 gene is on the X chromosome. We recorded baseline characteristics, comorbidities, prehospital ARBs or ACE inhibitor treatment, use of organ support and mortality, and measured RAS components at admission and days 2, 4, 7, and 14 in a subgroup ( n = 46), recorded d -dimer ( n = 967), comparing males with females.Setting: ARBs CORONA I is a multicenter Canadian observational cohort of patients hospitalized with acute COVID-19. This analysis includes patients admitted to 10 large urban hospitals across the four most populated provinces.Patients: One-thousand six-hundred eighty-six patients with polymerase chain reaction-confirmed COVID-19 (February 2020 to March 2021) for acute COVID-19 illness were included.Interventions: None.Measurements and Main Results: Males on ARBs before admission had decreased use of ventilation (adjusted odds ratio [aOR] = 0.52; p = 0.007) and vasopressors (aOR = 0.55; p = 0.011) compared with males not on ARBs or ACE inhibitors. No significant effects were observed in females for these outcomes. The test for interaction was significant for use of ventilation ( p = 0.006) and vasopressors ( p = 0.044) indicating significantly different responses to ARBs according to sex. Males had significantly higher plasma ACE-1 at baseline and angiotensin II at day 7 and 14 than females.Conclusions: ARBs use was associated with less ventilation and vasopressors in males but not females. Sex-based differences in RAS dysregulation may contribute to sex-based differences in outcomes and responses to ARBs in COVID-19. [ABSTRACT FROM AUTHOR]

Precise estimates of mortality in Staphylococcus aureus bacteraemia (SAB) are important to convey prognosis and guide the design of interventional studies. We performed a systematic review and meta-analysis to estimate all-cause mortality in SAB and explore mortality change over time. The MEDLINE and Embase databases, as well as the Cochrane Database of Systematic Reviews, were searched from January 1, 1991 to May 7, 2021. Human observational studies on patients with S. aureus bloodstream infection were included. The study analyzed data of patients with a positive blood culture for S. aureus. Two independent reviewers extracted study data and assessed risk of bias using the Newcastle–Ottawa Scale. A generalized, linear, mixed random effects model was used to pool estimates. A total of 341 studies were included, describing a total of 536,791 patients. From 2011 onward, the estimated mortality was 10.4% (95% CI, 9.0%–12.1%) at 7 days, 13.3% (95% CI, 11.1%–15.8%) at 2 weeks, 18.1% (95% CI, 16.3%–20.0%) at 1 month, 27.0% (95% CI, 21.5%–33.3%) at 3 months, and 30.2% (95% CI, 22.4%–39.3%) at 1 year. In a meta-regression model of 1-month mortality, methicillin-resistant S. aureus had a higher mortality rate (adjusted OR (aOR): 1.04; 95% CI, 1.02–1.06 per 10% increase in methicillin-resistant S. aureus proportion). Compared with prior to 2001, more recent time periods had a lower mortality rate (aOR: 0.88; 95% CI, 0.75–1.03 for 2001–2010; aOR: 0.82; 95% CI, 0.69–0.97 for 2011 onward). SAB mortality has decreased over the last 3 decades. However, more than one in four patients will die within 3 months, and continuous improvement in care remains necessary. [ABSTRACT FROM AUTHOR]

The article examines the potential rare adverse effects of proton pump inhibitors (PPI). It offers information on PPI which are widely prescribed for gastrointestinal diseases, however they must be given in the lowest dose and shortest duration. Several studies have reportedly revealed that long-term PPI use have serious adverse effects including hypomagnesemia. It also stresses the importance for physicians and patients to balance PPI use against potential benefits.

Background: Off-label use of gabapentinoids is common among patients admitted to hospital medical wards, who are at risk of adverse drug events. In this study, we will assess if educational brochures can increase rates of gabapentinoid deprescription among medical inpatients, compared with usual care. Methods: We describe the protocol for a prospective before-and-after trial that will take place on 5 medical wards of 2 tertiary care hospitals in Montréal, Canada. The study intervention will include distribution of educational brochures to users of gabapentinoids during hospital admission, as well as short educational sessions for medical staff on safe gabapentinoid prescribing practices. We will include patients with a gabapentinoid prescription before admission who are aged 60 years or older. Exclusion criteria are known seizure disorder, severe cognitive impairment, expected prognosis less than 3 months and inability to read English or French. The primary outcome is the rate of gabapentinoid deprescription at 8 weeks postdischarge. We aim to recruit 160 participants, with a 1:1 distribution between intervention and control groups. Interpretation: If successful, the use of educational brochures and staff education represents a scalable intervention to reduce gabapentinoid overuse by encouraging deprescription conversations between patients and their health care providers. Results of the study will be disseminated through publication in peer-reviewed journals and presentations at conferences. Trial registration: ClinicalTrials. gov, no. NCT04855578 [ABSTRACT FROM AUTHOR]

Background Deaths following Staphylococcus aureus bacteremia (SAB) may be related or unrelated to the infection. In SAB therapeutics research, the length of follow-up should be optimized to capture most attributable deaths and minimize nonattributable deaths. We performed a secondary analysis of a systematic review to describe attributable mortality in SAB over time. Methods We systematically searched Medline, Embase, and Cochrane Database of Systematic Reviews from 1 January 1991 to 7 May 2021 for human observational studies of SAB. To be included in this secondary analysis, the study must have reported attributable mortality. Two reviewers extracted study data and assessed risk of bias independently. Pooling of study estimates was not performed due to heterogeneity in the definition of attributable deaths. Results Twenty-four observational cohort studies were included. The median proportion of all-cause deaths that were attributable to SAB was 77% (interquartile range [IQR], 72%–89%) at 1 month and 62% (IQR, 58%–75%) at 3 months. At 1 year, this proportion was 57% in 1 study. In 2 studies that described the rate of increase in mortality over time, 2-week follow-up captured 68 of 79 (86%) and 48 of 57 (84%) attributable deaths that occurred by 3 months. By comparison, 1-month follow-up captured 54 of 57 (95%) and 56 of 60 (93%) attributable deaths that occurred by 3 months in 2 studies. Conclusions The proportion of deaths that are attributable to SAB decreases as follow-up lengthens. Follow-up duration between 1 and 3 months seems optimal if evaluating processes of care that impact SAB mortality. Clinical Trials Registration PROSPERO CRD42021253891. [ABSTRACT FROM AUTHOR]

Background: There have been multiple waves in the COVID-19 pandemic in many countries. We sought to compare mortality and respiratory, cardiovascular and renal dysfunction between waves in 3 Canadian provinces. Methods: We conducted a substudy of the ARBs CORONA I study, a multicentre Canadian pragmatic observational cohort study that examined the association of pre-existing use of angiotensin receptor blockers with outcomes in adults admitted to hospital with acute COVID-19 up to April 2021 from 9 community and teaching hospitals in 3 Canadian provinces (British Columbia, Ontario and Quebec). We excluded emergency department admissions without hospital admission, readmissions and admissions for another reason. We used logistic and 0–1-inflated β regression models to compare 28-day and in-hospital mortality, and the use of invasive mechanical ventilation, vasopressors and renal replacement therapy (RRT) between the first 3 waves of the COVID-19 pandemic in these provinces. Results: A total of 520, 572 and 245 patients in waves 1, 2 and 3, respectively, were included. Patients in wave 3 were on average younger and had fewer comorbidities than those in waves 1 and 2. The unadjusted 28-day mortality rate was significantly lower in wave 3 (7.8%) than in wave 1 (18.3%) (odds ratio [OR] 0.43, 95% confidence interval [CI] 0.24–0.78) and wave 2 (16.3%) (OR 0.46, 95% CI 0.27–0.79). After adjustment for differences in baseline characteristics, the difference in 28-day mortality remained significant (adjusted OR wave 3 v. wave 1: 0.46, 95% CI 0.26–0.81; wave 3 v. wave 2: 0.52, 95% CI 0.29–0.91). In-hospital mortality findings were similar. Use of invasive mechanical ventilation or vasopressors was less common in waves 2 and 3 than in wave 1, and use of RRT was less common in wave 3 than in wave 1. Interpretation: Severity of illness decreased (lower mortality and less use of organ support) across waves among patients admitted to hospital with acute COVID-19, possibly owing to changes in patient demographic characteristics and management, such as increased use of dexamethasone. Continued application of proven therapies may further improve outcomes. Study registration: ClinicalTrials.gov, no. NCT04510623 [ABSTRACT FROM AUTHOR]

Pneumocystis jirovecii pneumonia (PCP) is an opportunistic infection commonly affecting immunocompromised people. Diagnosis usually requires invasive techniques to obtain respiratory specimens. Minimally invasive detection tests have been proposed, but their operating characteristics are poorly described. To systematically review and meta-analyse the performance of minimally invasive PCP detection tests to inform diagnostic algorithms. Medline, Embase, Cochrane Library (inception to 15 October 2020). Studies of minimally invasive PCP detection tests were included if they contained a minimum of ten PCP cases. Adults at risk of PCP. Non-invasive PCP detection tests. Diagnosis using the combination of clinical and radiographical features with invasive sampling. Using the QUADAS-2 tool. We used bivariate and, when necessary, univariate analysis models to estimate diagnostic test sensitivity and specificity. Fifty-two studies were included; most studies (40) comprised exclusively human immunodeficiency virus (HIV) -infected individuals; nine were mixed (HIV and non-HIV), two were non-HIV and one study did not report HIV status. Sampling sites included induced sputum, nasopharyngeal aspirate, oral wash and blood. The four testing modalities evaluated were cytological staining, fluorescent antibody, PCR and lactate dehydrogenase. Induced sputum had the most data available; this modality was both highly sensitive at 99% (95% CI 51%–100%) and specific at 96% (95% CI 88%–99%). Induced sputum cytological staining had moderate sensitivity at 50% (95% CI 39%–61%) and high specificity at 100% (95% CI 100%–100%), as did fluorescent antibody testing with sensitivity 74% (95% CI 62%–87%) and specificity 100% (95% CI 91%–100%). There are several promising minimally invasive PCP diagnostic tests available, some of which may reduce the need for invasive respiratory sampling. Understanding the operating characteristics of these tests can augment current diagnostic strategies and help establish a more confident clinical diagnosis of PCP. Further studies in non-HIV infected populations are needed. [ABSTRACT FROM AUTHOR]

Pneumocystis jirovecii pneumonia (PCP) is a common opportunistic infection causing more than 400000 cases annually worldwide. Although antiretroviral therapy has reduced the burden of PCP in persons with human immunodeficiency virus (HIV), an increasing proportion of cases occur in other immunocompromised populations. In this review, we synthesize the available randomized controlled trial (RCT) evidence base for PCP treatment. We identified 14 RCTs that were conducted 25–35 years ago, principally in 40-year-old men with HIV. Trimethoprim-sulfamethoxazole, at a dose of 15–20 mg/kg per day, is the treatment of choice based on historical practice rather than on quality comparative, dose-finding studies. Treatment duration is similarly based on historical practice and is not evidence based. Corticosteroids have a demonstrated role in hypoxemic patients with HIV but have yet to be studied in RCTs as an adjunctive therapy in non-HIV populations. The echinocandins are potential synergistic treatments in need of further investigation. [ABSTRACT FROM AUTHOR]

Differentiating cellulitis from pseudocellulitis is challenging, and misdiagnosis leads to unnecessary antimicrobial use and increased healthcare expenditure. Clinical diagnosis remains the criterion standard and may involve expert consultation. Our objective was to evaluate the usefulness of a handheld infrared thermometer to improve diagnostic certainty in cases of suspected cellulitis. We conducted a cross-sectional study from August 2018 to January 2020 at a tertiary-care hospital in Montreal, Canada. We enrolled adult patients with suspected limb cellulitis. Using the infrared thermometer, we compared the average temperature of the affected area with that of the contralateral limb, and we used Youden's method to determine the optimal temperature difference which best differentiated cellulitis from pseudocellulitis as determined by an independent and blinded infectious diseases specialist. We used bootstrapping to estimate 95% confidence intervals for the sensitivity, specificity, and area under the receiver operating curve. Of 65 patients screened for enrolment, 52 patients were recruited (median age: 64 years, IQR 52–76); 39 of these were diagnosed with cellulitis and 13 were not. The mean temperature difference between affected and unaffected limbs was 2.6°C (95%CI 2.1–3.1°C) for patients with cellulitis and 0.4°C (95%CI –1.2°C to 2.1°C) for patients without (p < 0.001). An average temperature difference between limbs of 0.8°C or more was 95% sensitive (95%CI 74–100%) and 69% specific (95%CI 44–95%) for the diagnosis of cellulitis (c-statistic 0.82). In this proof-of-concept single-centre study, a handheld infrared thermometer was a useful aid to differentiate cellulitis from pseudocellulitis. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 62-year-old man with a one week history of fever and confusion. The patient was diagnosed with nocardiosis after skin and brain biopsies, which revealed filamentous gram-positive bacilli, consistent with nocardiosis. It says that the mental status of the patient gradually improved and his skin lesion disappeared after the administration of combined therapy with trimethoprim-sulfamethoxazole and meropenem, with substantial resolution of brain lesions.

Background + Objectives: The echinocandins, amphotericin B preparations, voriconazole and fluconazole are approved for the treatment of invasive candidiasis, though it remains unclear which agent is most effective. In order to answer this question, we performed a systematic review and network meta‐analysis of the randomised controlled trials (RCTs) which evaluated these agents in comparison. Methods: Four electronic databases were searched from database inception to 8 October 2020. RCTs comparing triazoles, echinocandins or amphotericin B for the treatment of invasive candidiasis or candidemia were included. Random effect Bayesian network meta‐analysis methods were used to compare treatment outcomes. Results: Thirteen RCTs met inclusion criteria. Of the 3528 patients included from these trials, 1531 were randomised to receive an echinocandin, 944 to amphotericin B and 1053 to a triazole. For all forms of invasive candidiasis, echinocandins were associated with the highest rate of treatment success when compared to amphotericin B (OR 1.41, 95% CI 1.04–1.92) and the triazoles (OR 1.82, 95% CI 1.35–2.51). Rank probability analysis favoured echinocandins as the most effective choice 98% of the time. Overall survival did not significantly differ between groups. Conclusions: Among patients with invasive candidiasis, echinocandins had the best clinical outcomes and should remain the first‐line agents in the treatment of invasive candidiasis. [ABSTRACT FROM AUTHOR]

Plasma anti-SARS-CoV2 IgG, IgA, and IgM antibody isotypes were quantified, and changes in their concentrations from day 4 to 7 were investigated for association with mortality and use of ventilation or vasopressors. In conclusion, in acute COVID-19 hospitalized patients, the concentrations of IgG, IgA, and IgM binding antibodies against SARS-CoV-2 increased significantly from day 4 to day 7. [Extracted from the article]

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a rapidly emerging virus causing the ongoing coronavirus disease 2019 (COVID-19) pandemic with no known effective prophylaxis. We investigated whether hydroxychloroquine could prevent SARS-CoV-2 in healthcare workers at high risk of exposure. Methods We conducted a randomized, double-blind, placebo-controlled clinical trial of healthcare workers with ongoing exposure to persons with SARS-CoV-2, including those working in emergency departments, intensive care units, COVID-19 hospital wards, and first responders. Participants across the United States and in the Canadian province of Manitoba were randomized to hydroxychloroquine loading dose then 400 mg once or twice weekly for 12 weeks. The primary endpoint was confirmed or probable COVID-19–compatible illness. We measured hydroxychloroquine whole-blood concentrations. Results We enrolled 1483 healthcare workers, of whom 79% reported performing aerosol-generating procedures. The incidence of COVID-19 (laboratory-confirmed or symptomatic compatible illness) was 0.27 events/person-year with once-weekly and 0.28 events/person-year with twice-weekly hydroxychloroquine compared with 0.38 events/person-year with placebo. For once-weekly hydroxychloroquine prophylaxis, the hazard ratio was.72 (95% CI,.44–1.16; P =.18) and for twice-weekly was.74 (95% CI,.46–1.19; P =.22) compared with placebo. Median hydroxychloroquine concentrations in whole blood were 98 ng/mL (IQR, 82–120) with once-weekly and 200 ng/mL (IQR, 159–258) with twice-weekly dosing. Hydroxychloroquine concentrations did not differ between participants who developed COVID-19–compatible illness (154 ng/mL) versus participants without COVID-19 (133 ng/mL; P =.08). Conclusions Pre-exposure prophylaxis with hydroxychloroquine once or twice weekly did not significantly reduce laboratory-confirmed COVID-19 or COVID-19–compatible illness among healthcare workers. Clinical Trials Registration Clinicaltrials.gov NCT04328467. [ABSTRACT FROM AUTHOR]

Background Bloodstream infections (BSIs) with methicillin-susceptible Staphylococcus aureus (MSSA) are associated with significant morbidity and mortality. Our objective in this study was to determine the efficacy of synergistic treatment with daptomycin when given with either cefazolin or cloxacillin for the treatment of MSSA BSI. Methods A randomized, double-blind, placebo-controlled trial was performed at 2 academic hospitals in Montreal, Canada. Patients aged ≥18 years with MSSA BSI receiving either cefazolin or cloxacillin monotherapy were considered for inclusion. In addition to the standard-of-care treatment, participants received a 5-day course of adjunctive daptomycin or placebo. The primary outcome was the duration of MSSA BSI in days. Results Of 318 participants screened, 115 were enrolled and 104 were included in the intention-to-treat analysis (median age, 67 years; 34.5% female). The median duration of bacteremia was 2.04 days among patients who received daptomycin vs 1.65 days in those who received placebo (absolute difference, 0.39 days; P  = .40). In a modified intention-to-treat analysis that involved participants who remained bacteremic at the time of enrollment, we found a median duration of bacteremia of 3.06 days among patients who received daptomycin vs 3.0 days in those who received placebo (absolute difference, 0.06 days; P  = .77). Ninety-day mortality in the daptomycin arm was 18.9% vs 17.7% in the placebo arm (P  = 1.0). Conclusions Among patients with MSSA BSIs, the administration of adjunctive daptomycin therapy to standard-of-care treatment did not shorten the duration of bacteremia and should not be routinely considered. Clinical Trials Registration NCT02972983. [ABSTRACT FROM AUTHOR]

Proton pump inhibitor (PPI) therapy is a potentially modifiable risk factor for recurrent Clostridioides difficile infection (CDI). Citing an absence of clinical trials, many guidelines do not provide recommendations for addressing PPI management. Our aim was to perform an updated systematic review and meta-analysis evaluating the association between PPI use and recurrent CDI addressing prior methodological limitations. Data sources were MEDLINE and EMBASE. Eligible studies were cohort and case–control studies; there were no restrictions on study setting or duration of follow-up. Participants were adults with prior CDI who did or did not receive PPI therapy and were assessed for recurrent CDI. Summary (unadjusted) odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random effects model. Prespecified subgroup analyses were performed to explore heterogeneity including study design, study quality, duration of follow-up, adjustment for confounders, and outcome definition. Sixteen studies were included in the meta-analysis, comprising 57 477 patients with CDI, of whom 6870 (12%) received PPIs. The rate of recurrent CDI was 24% in patients treated with PPIs versus 18% in those who were not. A meta-analysis that pooled unadjusted odds ratios demonstrated higher odds of recurrent CDI in patients who received PPIs (OR 1.69, 95%CI 1.46–1.96) versus those who did not. There was moderate heterogeneity between studies (I2 56%); however, a sensitivity analysis restricted to studies with 56 days of follow-up substantially reduced the heterogeneity (OR 1.59, 95%CI 1.36–1.85; I2 12%). An analysis restricted to multivariate studies that combined adjusted ORs also demonstrated higher odds of recurrent CDI in patients who received PPIs (OR 1.49, 95%CI 1.12–2.00). No publication bias was identified. We found significantly higher odds of recurrent CDI among users of PPIs that persisted across multiple sensitivity analyses. These results support stronger recommendations for PPI stewardship at CDI diagnosis. [ABSTRACT FROM AUTHOR]

Objectives The US Food and Drug Administration licensed ezetimibe in 2002 because of its ability to lower low-density lipoprotein cholesterol levels, a surrogate marker for the risk of coronary artery disease. The negative results of the Effect of Ezetimibe Plus Simvastatin Versus Simvastatin Alone on Atherosclerosis in the Carotid Artery trial were published in 2008. Since then, we have seen 6 additional years without a landmark study in favor of ezetimibe. Furthermore, the new American Heart Association/American College of Cardiology guidelines (2013) now strongly downplay the use of nonstatin agents. We sought to determine whether ezetimibe use remains common in 2014 using a new cohort that we have created to teach residents how to perform clinically relevant research. Methods The McGill Teaching Unit Cohort is an anonymized prospective cohort study enrolling all patients admitted to the medical clinical teaching units of the Royal Victoria Hospital in Montréal, Québec, Canada, as of 2014. Information collected includes the receipt of cholesterol-lowering medications and other important demographics. Results Of the 783 patients enrolled on the date of analysis, 331 (42.7%) were receiving treatment for hypercholesterolemia. Of these, 156 (47%) were receiving primary prophylaxis. Overall, 323 patients (98%) were receiving a statin, 17 patients (5.1%) were receiving ezetimibe, and 5 patients (1.5%) were receiving a fibrate. Users of ezetimibe were more likely to be active smokers than nonusers (6/17 vs 42/314, P = .01); however, there were no other significant differences between important covariates or recent low-density lipoprotein measurements. Conclusions Ezetimibe use remains common amongst medical inpatients despite a lack of evidence supporting its efficacy. [ABSTRACT FROM AUTHOR]

Background Nephrotoxicity is a known adverse effect of polymyxin antibiotics, including colistin. Although previous meta-analyses have aimed to characterize colistin-associated nephrotoxicity risk relative to other antibiotics, included studies were observational in nature with high risk of confounding and heterogeneity. We conducted this systematic review and meta-analysis of exclusively randomized controlled trials (RCTs) to evaluate the incidence of nephrotoxicity associated with colistin versus minimally nephrotoxic antibiotics. Methods We searched PubMed, EMBASE, Cochrane Library, and 3 trial registries for RCTs comparing the nephrotoxicity of colistin to nonpolymyxin antibiotics. Randomized controlled trials that used aminoglycosides were excluded. Risk ratios (RRs) and 95% confidence intervals (CIs) were calculated using random-effects models. The study outcome was the rate of nephrotoxicity. Results Five RCTs with a total of 377 patients were included. Most patients received colistin for pneumonia in the intensive care unit, and the comparators were β-lactam-based regimens. Colistimethate sodium was dosed at 9 million units/day (300 mg/day of colistin base activity), with administration of a loading dose in 4 studies. The nephrotoxicity incidence in patients who received colistin was 36.2% (95% CI, 23.3% to 51.3%). The nephrotoxicity rate was significantly higher in the colistin arm than comparators (RR, 2.40; 95% CI, 1.47 to 3.91; P ≤.001; I2 = 0%), and the number needed to harm was 5. Findings persisted upon one-study-removed-analysis. Conclusions This meta-analysis of RCTs found a colistin-associated nephrotoxicity rate of 36.2% and an increase in this risk compared with β-lactam-based regimens by 140%. Colistin should be regarded as a last-line agent and safer alternatives should be considered when possible. [ABSTRACT FROM AUTHOR]

As the severe acute respiratory syndrome coronavirus 2 pandemic evolved, it was apparent that well designed and rapidly conducted randomized clinical trials were urgently needed. However, traditional clinical trial design presented several challenges. Notably, disease prevalence initially varied by time and region, and the pockets of outbreaks evolved geographically over time. Coupled with an occupational hazard from in-person study visits, timely recruitment would prove difficult in a traditional in-person clinical trial. Thus, our team opted to launch nationwide internet-based clinical trials using patient-reported outcome measures. In total, 2795 participants were recruited using traditional and social media, with screening and enrollment performed via an online data capture system. Follow-up surveys and survey reminders were similarly managed through this online system with manual participant outreach in the event of missing data. In this report, we present a narrative of our experience running internet-based clinical trials and provide recommendations for the design of future clinical trials during a world pandemic. [ABSTRACT FROM AUTHOR]

Background The effect of participation in a clinical trial on concomitant off-study investigational drug use has not been described. We sought to determine if participation in the Daptomycin as Adjunctive Therapy for Staphylococcus aureus bacteremia (DASH) trial increased overall daptomycin prescribing at study sites. Methods We retrospectively analyzed daptomycin use for 8 years preceding the trial, off-study daptomycin use during the trial itself (31 months), and daptomycin use for 6 fiscal months after trial completion. We used a segmented linear regression analysis of an interrupted time series to analyze changes in each drug's defined daily doses (DDD) per 1000 patient-days. As a control, we analyzed use of linezolid over these periods and also accounted for rates of methicillin-resistant S. aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) infections. Results For 1.5 years before the DASH trial, daptomycin use was decreasing by –0.30 DDD per 1000 patient-days per fiscal period (95% CI, –0.52 to –0.07). Following the initiation of the study, there was a statistically significant increase in daptomycin use of 0.28 DDD per 1000 patient-days per fiscal period (95% CI, 0.03 to 0.52), despite low, stable rates of MRSA and VRE infections. Following trial completion, daptomycin use decreased back toward prestudy rates. Use of linezolid remained stable throughout. Conclusions Despite the DASH trial being a negative study, it impacted the prescribing habits of local clinicians during recruitment. Trialists should be aware of potential off-target study effects, and prescribers should be wary of early uptake of interventions before definitive study results. [ABSTRACT FROM AUTHOR]

Background: Syndromic surveillance through web or phone-based polling has been used to track the course of infectious diseases worldwide. Our study objective was to describe the characteristics, symptoms, and self-reported testing rates of respondents in three different COVID-19 symptom surveys in Canada. Methods: This was a cross-sectional study using three distinct Canada-wide web-based surveys, and phone polling in Ontario. All three sources contained self-reported information on COVID-19 symptoms and testing. In addition to describing respondent characteristics, we examined symptom frequency and the testing rate among the symptomatic, as well as rates of symptoms and testing across respondent groups. Results: We found that over March- April 2020, 1.6% of respondents experienced a symptom on the day of their survey, 15% of Ontario households had a symptom in the previous week, and 44% of Canada-wide respondents had a symptom in the previous month. Across the three surveys, SARS-CoV-2-testing was reported in 2–9% of symptomatic responses. Women, younger and middle-aged adults (versus older adults) and Indigenous/First nations/Inuit/Métis were more likely to report at least one symptom, and visible minorities were more likely to report the combination of fever with cough or shortness of breath. Interpretation: The low rate of testing among those reporting symptoms suggests significant opportunity to expand testing among community-dwelling residents of Canada. Syndromic surveillance data can supplement public health reports and provide much-needed context to gauge the adequacy of SARS-CoV-2 testing rates. [ABSTRACT FROM AUTHOR]

Pneumocystis jirovecii pneumonia (PJP) can be a life-threatening opportunistic infection in immunocompromised hosts. The diagnosis can be challenging, often requiring semi-invasive respiratory sampling. The serum 1,3-β-D-glucan (BDG) assay has been proposed as a minimally invasive test for the presumptive diagnosis of PJP. We carried out a systematic review and meta-analysis using articles in the English language published between January 1960 and September 2019. We estimated the pooled sensitivity and specificity of BDG testing using a bivariate random effects approach and compared test performance in human immunodeficiency virus (HIV) and non-HIV subgroups with meta-regression. Data from the pooled sensitivity and specificity were transformed to generate pre- and post-test probability curves. Twenty-three studies were included. The pooled sensitivity and specificity of serum BDG testing for PJP were 91% (95%CI 87–94%) and 79% (95%CI 72–84%) respectively. The sensitivity in patients with HIV was better than in patients without (94%, 95%CI 91–96%) versus 86% (95%CI 78–91%) (p 0.02), with comparable specificity (83%, 95%CI 69–92% versus 83%, 95%CI 72–90%) (p 0.10). A negative BDG was only associated with a low post-test probability of PJP (≤5%) when the pre-test probability was low to intermediate (≤20% in non-HIV and ≤50% in HIV). Among patients with a higher likelihood of PJP, the pooled sensitivity of BDG is insufficient to exclude infection. Similarly, for most cases, the pooled specificity is inadequate to diagnose PJP. Understanding the performance of BDG in the population being investigated is therefore essential to optimal clinical decision-making. [ABSTRACT FROM AUTHOR]

BACKGROUND/OBJECTIVES Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection causes high morbidity and mortality in older adults with chronic illnesses. Several trials are currently underway evaluating the antimalarial drug hydroxychloroquine as a potential treatment for acute infection. However, polypharmacy predisposes patients to increased risk of drug‐drug interactions with hydroxychloroquine and may render many in this population ineligible to participate in trials. We aimed to quantify the degree of polypharmacy and burden of potentially inappropriate medications (PIMs) that older hospitalized adults are taking that would interact with hydroxychloroquine. METHODS: We reanalyzed data from the cohort of patients 65 years and older enrolled in the MedSafer pilot study. We first identified patients taking medications with potentially harmful drug‐drug interactions with hydroxychloroquine that might exclude them from participation in a typical 2019 coronavirus disease (COVID‐19) therapeutic trial. Next, we identified medications that were flagged by MedSafer as potentially inappropriate and crafted guidance around medication management if contemplating the use of hydroxychloroquine. RESULTS: The cohort contained a total of 1,001 unique patients with complete data on their home medications at admission. Of these 1,001 patients, 590 (58.9%) were receiving one or more home medications that could potentially interact with hydroxychloroquine, and of these, 255 (43.2%) were flagged as potentially inappropriate by the MedSafer tool. Common classes of PIMs observed were antipsychotics, cardiac medications, and antidiabetic agents. CONCLUSION: The COVID‐19 pandemic highlights the importance of medication optimization and deprescribing PIMs in older adults. By acting now to reduce polypharmacy and use of PIMs, we can better prepare this vulnerable population for inclusion in trials and, if substantiated, pharmacologic treatment or prevention of COVID‐19. J Am Geriatr Soc 68:1636‐1646, 2020. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the hypothesis that nonadherence to medication changes made at hospital discharge is associated with an increased risk of adverse events in the 30 days postdischarge.Study Setting: Patients admitted to hospitals in Montreal, Quebec, between 2014 and 2016.Study Design: Prospective cohort study.Data Collection: Nonadherence to medication changes was measured by comparing medications dispensed in the community with those prescribed at hospital discharge. Patient, health system, and drug regimen-level covariates were measured using medical services and pharmacy claims data as well as data abstracted from the patient's hospital chart. Multivariable Cox models were used to determine the association between nonadherence to medication changes and the risk of adverse events.Principal Findings: Among 2655 patients who met our inclusion criteria, mean age was 69.5 years (SD 14.7) and 1581 (60%) were males. Almost half of patients (n = 1161, 44%) were nonadherent to at least one medication change, and 860 (32%) were readmitted to hospital, visited the emergency department, or died in the 30 days postdischarge. Patients who were not adherent to any of their medication changes had a 35% higher risk of adverse events compared to those who were adherent to all medication changes (1.41 vs 1.27 events/100 person-days, adjusted hazard ratio: 1.35, 95% CI: 1.06-1.71).Conclusions: Almost half of all patients were not adherent to some or all changes made to their medications at hospital discharge. Nonadherence to all changes was associated with an increased risk of adverse events. Interventions addressing barriers to adherence should be considered moving forward. [ABSTRACT FROM AUTHOR]

Background: Pneumocystis jirovecii pneumonia (PJP) can be challenging to diagnose, often requiring bronchoscopy. Since most patients suspected of PJP undergo imaging, we hypothesized that the findings of these studies could help estimate the probability of disease prior to invasive testing.Methods: We created a cohort of patients who underwent bronchoscopy specifically to diagnose PJP and conducted a nested case-control study to compare the radiographic features between patients with (n = 72) and without (n = 288) pathologically proven PJP. We used multivariable logistic regression to identify radiographic features independently associated with PJP.Results: Chest x-ray findings poorly predicted the diagnosis of PJP. However, multivariable analysis of CT scan findings found that "increased interstitial markings" (OR 4.3; 95%CI 2.2-8.2), "ground glass opacities" (OR 3.3; 95%CI 1.2-9.1) and the radiologist's impression of PJP being "possible" (OR 2.0; 95%CI 1.0-4.1) or "likely" (OR 9.3; 95%CI 3.4-25.3) were independently associated with the final diagnosis (c-statistic 0.75).Conclusions: Where there is clinical suspicion of PJP, the use of CT scan can help determine the probability of PJP. Identifying patients at low risk of PJP may enable better use of non-invasive testing to avoid bronchoscopy while higher probability patients could be prioritized. [ABSTRACT FROM AUTHOR]

OBJECTIVES Polypharmacy is common in older adults and associated with adverse drug events (ADEs). Several methods have been described in studies to help correlate ADE causation. We performed a narrative review to identify methods for ADE adjudication. We compared their strengths and limitations to assess their applicability to deprescribing studies (of which clinical trials are a subset) and to encourage the use of a standardized method in future studies. DESIGN: We performed a review of original articles (1946‐2019) using the Medline (Ovid) and Cochrane databases. We also conducted a manual reference search of review articles. Abstracts were screened for relevance. MEASUREMENTS: Adjudication methods were compared for advantages and limitations including validity, ease of use, and applicability to clinical trials with deprescribing as the primary intervention. RESULTS: The search yielded 1881 articles of which 175 articles were included for full‐text review. Following in‐depth review, 135 were excluded: 79 had no ADE outcome data, 35 were not specific to older adults, 9 were not relevant, 6 were review articles, 5 contained duplicate data, and 1 was not written in French or English. Forty articles remained for analysis, from which we identified 10 unique ADE adjudication methods. No method was developed originally for use in a deprescribing setting. CONCLUSION: A standard method to identify ADEs is important to capture the outcome reliably in deprescribing studies. All methods we identified had limitations in terms of capturing adverse events from the withdrawal of medications. Future work should focus on refining adjudication methods for capturing ADEs related not only to medication continuation and new drug starts but also to deprescribing and drug discontinuation. J Am Geriatr Soc 68:1594‐1602, 2020. [ABSTRACT FROM AUTHOR]

Background Pneumocystis jirovecii pneumonia (PJP) remains a common and highly morbid infection for immunocompromised patients. Trimethoprim-sulfamethoxazole (TMP-SMX) is the antimicrobial treatment of choice. However, treatment with TMP-SMX can lead to significant dose-dependent renal and hematologic adverse events. Although TMP-SMX is conventionally dosed at 15–20 mg/kg/d of trimethoprim for the treatment of PJP, reduced doses may be effective and carry an improved safety profile. Methods We conducted a systematic search in the Medline, Embase, and Cochrane Library databases from inception through March 2019 for peer-reviewed studies reporting on reduced doses of TMP-SMX (15 mg/kg/d of trimethoprim or less) for the treatment of PJP. PRISMA, MOOSE, and Cochrane guidelines were followed. Gray literature was excluded. Results Ten studies were identified, and 6 were included in the meta-analysis. When comparing standard doses with reduced doses of TMP-SMX, there was no statistically significant difference in mortality (absolute risk difference, –9% in favor of reduced dose; 95% confidence interval [CI], –27% to 8%). When compared with standard doses, reduced doses of TMP-SMX were associated with an 18% (95% CI, –31% to –5%) absolute risk reduction of grade ≥3 adverse events. Conclusions In this systematic review, treatment of PJP with doses of ≤10 mg/kg/d of trimethoprim was associated with similar rates of mortality when compared with standard doses and with significantly fewer treatment-emergent severe adverse events. Although limited by the observational nature of the studies included, this review provides the most current available evidence for the optimal dosing of TMP-SMX in the treatment of PJP. [ABSTRACT FROM AUTHOR]

Background: Double carbapenem therapy has been promoted as an alternative treatment for infections due to carbapenemase-producing Enterobacteriaceae where carbapenemase inhibitors are unavailable or when other agents have demonstrated toxicity with equally limited evidence. The capacity of other β-lactams and β-lactamase inhibitors to provide synergistic activity with carbapenems is unclear.Objectives: This study sought to investigate the in vitro synergistic potential of other β-lactam/β-lactamase combinations with meropenem against KPC producers.Methods: Time-kill assays were performed on 24 unique strains of KPC-producing Klebsiella pneumoniae. Combinations evaluated included meropenem or imipenem with one of the following: ertapenem, piperacillin/tazobactam or ceftolozane/tazobactam. Concentrations used for each drug were those considered physiologically attainable in patients with a time above the concentration exceeding 40%-50% of the dose interval. Combinations were considered to be synergistic when they reduced bacterial cfu/mL by ≥2 log10 at 24 h as compared with the single most active agent.Results: The combination of piperacillin/tazobactam with meropenem was found to be synergistic against 70.8% of the isolates, followed by ertapenem with meropenem (58.3%) and ceftolozane/tazobactam with meropenem (41.7%). The piperacillin/tazobactam combination was found to be more bactericidal than the other combinations, with 58.3% of isolates demonstrating a ≥4 log10 cfu/mL reduction at 24 h, as compared with 37.5% for ertapenem and 20.8% for ceftolozane/tazobactam combinations.Conclusions: The combination of piperacillin/tazobactam with meropenem may be a potential therapy against KPC-producing K. pneumoniae when other therapies are unavailable or prohibitively toxic. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Polypharmacy is common, costly, and harmful for hospitalized older adults. Scalable strategies to reduce the burden of potentially inappropriate medications (PIMs) are needed. We sought to leverage medication reconciliation in hospitalized older adults by pairing with MedSafer, an electronic decision support tool for deprescribing. DESIGN: This was a nonrandomized controlled before‐and‐after study. SETTING: The study took place on four internal medicine clinical teaching units. PARTICIPANTS: Subjects were aged 65 years and older, had an expected prognosis of 3 or more months, and were taking five or more usual home medications. INTERVENTION: In the baseline phase, patients received usual care that was medication reconciliation. Patients in the intervention arm also had a "deprescribing opportunity report" generated by MedSafer and provided to their in‐hospital treating team. MEASUREMENTS: The primary outcome was ascertained at the time of hospital discharge and was the proportion of patients who had one or more PIMs deprescribed. RESULTS: A total of 1066 patients were enrolled, and deprescribing opportunities were present for 873 (82%; 418 during the control and 455 during the intervention phases, respectively). The proportion of patients with one or more PIMs deprescribed at discharge increased from 46.9% in the control period to 54.7% in the intervention period with an adjusted absolute risk difference of 8.3% (2.9%‐13.9%). Not all classes of drugs in the intervention arm were associated with an increase in deprescribing, and new PIM starts were equally common in both arms of the study. CONCLUSION: Using an electronic decision support tool for deprescribing, we increased the proportion of patients with one or more PIMs deprescribed at hospital discharge as compared with usual care. Although this type of intervention may help address medication overload in hospitalized patients, it also underscores the importance of powering future trials for a reduction in adverse drug events. Trial registration: NCT02918058. J Am Geriatr Soc 67:1843–1850, 2019 [ABSTRACT FROM AUTHOR]

Background Current guidelines recommend the use of echinocandins, amphotericin B or fluconazole for the treatment of invasive candidiasis and candidemia. The objective of our study was to compare these agents through a systematic review of the literature and network meta-analysis of randomized controlled trials. Methods Three electronic databases (Medline, PubMed, and the Cochrane Database of Systematic Reviews) were searched from database inception to January 1 2019. Randomized controlled trials that compared triazoles, echinocandins and/or amphotericin B (either in lipid formulation or deoxycholate form) for the treatment of invasive candidiasis or candidemia were included. Among included studies, treatment success was collected as the primary outcome and was assessed by a random effect network meta-analysis using Bayesian estimation methods. A sensitivity analysis was performed for all patients with candidemia. Results Eleven randomized controlled trials met the study inclusion criteria. Of the 2,475 patients included from these trials, 684 received an echinocandin, 855 received amphotericin B and 936 received a triazole. Echinocandins were associated with the highest rate of treatment success when compared with amphotericin B (OR 1.40, 95% CI 1.02–1.93) and the triazoles (OR 1.80, 95% CI 1.32–2.51). Similarly, in the pre-specified analysis of candidemic patients, echinocandins were also more effective overall than amphotericin B (OR 1.25, 95% CI 0.84–1.87) and triazoles (OR 1.66, 95% CI 1.16–2.44). Patients treated with triazoles had a lower rate of treatment success than amphotericin B in the overall (OR 0.78, 95% CI 0.60–1.01) and candidemia sensitivity analyses (OR 0.76, 95% CI 0.56–1.01) Rank probability analysis favored echinocandins as the most effective treatment choice 98% of the time. Conclusion In our meta-analysis comparing treatment strategies for severe Candida infections, the echinocandins had the highest rate of treatment success compared with both amphotericin B and triazoles. Echinocandins should be considered as first-line agents in the treatment of invasive candidiasis and candidemia. Further research is needed to determine the minimum duration of echinocandin treatment prior to using step-down therapy. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Efficacy of oral vancomycin in preventing recurrent Clostridium difficile infection in patients treated with systemic antimicrobial agents" by N.W. Van Hise and others, published in a 2016 issue.

In multivariable analysis of associations between initial antibiotic therapy and clinical outcomes in 5005 patients with microbiologically confirmed Streptococcus pneumoniae infections,"discordant" empiric antibiotic therapy was not associated with 30-day mortality rate (hazard ratio, 0.94; 95% confidence interval, .67-1.32). [ABSTRACT FROM AUTHOR]

Background: Adverse events (AEs) in acute care hospitals are frequent and associated with significant morbidity, mortality, and costs. Measuring AEs is necessary for quality improvement and benchmarking purposes, but current detection methods lack in accuracy, efficiency, and generalizability. The growing availability of electronic health records (EHR) and the development of natural language processing techniques for encoding narrative data offer an opportunity to develop potentially better methods. The purpose of this study is to determine the accuracy and generalizability of using automated methods for detecting three high-incidence and high-impact AEs from EHR data: a) hospital-acquired pneumonia, b) ventilator-associated event and, c) central line-associated bloodstream infection.Methods: This validation study will be conducted among medical, surgical and ICU patients admitted between 2013 and 2016 to the Centre hospitalier universitaire de Sherbrooke (CHUS) and the McGill University Health Centre (MUHC), which has both French and English sites. A random 60% sample of CHUS patients will be used for model development purposes (cohort 1, development set). Using a random sample of these patients, a reference standard assessment of their medical chart will be performed. Multivariate logistic regression and the area under the curve (AUC) will be employed to iteratively develop and optimize three automated AE detection models (i.e., one per AE of interest) using EHR data from the CHUS. These models will then be validated on a random sample of the remaining 40% of CHUS patients (cohort 1, internal validation set) using chart review to assess accuracy. The most accurate models developed and validated at the CHUS will then be applied to EHR data from a random sample of patients admitted to the MUHC French site (cohort 2) and English site (cohort 3)-a critical requirement given the use of narrative data -, and accuracy will be assessed using chart review. Generalizability will be determined by comparing AUCs from cohorts 2 and 3 to those from cohort 1.Discussion: This study will likely produce more accurate and efficient measures of AEs. These measures could be used to assess the incidence rates of AEs, evaluate the success of preventive interventions, or benchmark performance across hospitals. [ABSTRACT FROM AUTHOR]