Chloramphenicol versus ceftriaxone for the treatment of pneumonia and sepsis in elderly patients with advanced dementia and functional disability. A propensity-weighted retrospective cohort study.

BACKGROUND: Sepsis and pneumonia in the elderly comprise a significant portion of medical admissions. Chloramphenicol has been used in Israel for treatment of bacterial infections, without evidence regarding its efficacy and safety. OBJECTIVES: We aimed to examine whether chloramphenicol was associated with similar outcomes to ceftriaxone, for treatment of sepsis and pneumonia in the elderly with dementia and functional disability. METHODS: Patients over 75, with dementia and functional disability, admitted to the internal medicine ward at Beilinson Hospital between 2011 and 2021, with community-acquired aspiration pneumonia or sepsis of undetermined source were included. Patients with mild dementia and independent in their activities of daily living were excluded. Primary outcome was 30- and 90-day all-cause mortality. A propensity-weighted multivariable model was constructed using inverse probability of treatment weighting. Results were expressed as OR with 95% CI. RESULTS: In total, 1558 patients were included: 512 treated with chloramphenicol and 1046 with ceftriaxone. The cohort consisted of elderly patients (mean age 87 ±â€Š6.2 years) with comorbidities; 30- and 90-day all-cause mortality were similar [222/512 (43.3%) versus 439/1046 (41.9%) P = 0.602, and 261/512 (50.9%) versus 556/1046 (53.1%) P = 0.419, respectively]. Propensity-weighted, logistic multivariable analysis for 30- and 90-day all-cause mortality revealed similar mortality rates for chloramphenicol and ceftriaxone (OR 1.049 95% CI 0.217-1.158, OR 0.923 95% CI 0.734-1.112, respectively). CONCLUSION: In this retrospective cohort of elderly debilitated patients hospitalized with pneumonia and sepsis, we found no difference in 30- and 90-day mortality between those treated with chloramphenicol or ceftriaxone. Further studies should determine the efficacy and safety of chloramphenicol in this population.

The yield of F18 FDG PET-CT for the investigation of fever of unknown origin, compared with diagnostic CT.

BACKGROUND: 18F-Fluoro-2-deoxy-D-glucose (FDG) positron emission tomography, with contrast enhanced CT (PET-CT), is recommended as a first or a second-line imaging method for the evaluation of patients with fever of unknown origin (FUO). We evaluated the yield of PET-CT vs. contrast enhanced CT (alone) for the diagnosis of classical FUO. METHODS: A single center, 8-year retrospective cohort study. All hospitalized patients who underwent PET-CT for the investigation of classical FUO between 1/2012-1/2020 were included. The final diagnosis, based on clinical, microbiological, radiological and pathological data available at the latest follow-up, at least six months after discharge, was determined. For each case, we determined whether the diagnosis would have been reached based on the CT scan alone, or based on the PET-CT (thus, defining PET-CT as necessary). We compared the overall sensitivity and specificity results for both PET-CT and CT scan. Variables that were found to be significantly associated with PET-CT necessity on univariable analysis were entered into a multivariable logistic regression analysis. The results of the regression model were reported in odds ratios (OR) and 95% confidence intervals (CI). RESULT: A total of 303 patients with classical FUO were referred for PET-CT. The final diagnoses included infectious diseases in 111/303 patients (36.5%), malignancies in 56/303 patients (18.4%) and non-infectious inflammatory conditions in 52/303 patients (17.1%). FUO resolved without diagnosis in 84/303 patients (28%). The overall sensitivity and specificity of the PET-CT scans were 88.7% and 80.9%, respectively, and for the CT scans were 75.2% and 90.2%, respectively. PET-CT had superior sensitivity vs CT (p=0.00) for all subgroups, with generally decreased specificity than CT for infections and inflammatory conditions. PET-CT was determined as necessary in 26% (79/303) of the patients. Endovascular infection, hematological malignancy and large vessel vasculitis were the only factors associated with PET-CT necessity on multivariable analysis. CONCLUSIONS: PET-CT offers superior sensitivity with slightly decreased specificity for the diagnosis of classical FUO compared to diagnostic CT. We recommend PET-CT as the imaging modality of choice for patients with classical FUO, when endovascular infection, hematological malignancy or large vessel vasculitis are suspected.

Tocilizumab in the treatment of COVID-19-a meta-analysis.

BACKGROUND: Interleukin-6 inhibitors showed promising results in observational trials of patients with coronavirus disease 2019 (COVID-19). AIM: To evaluate whether interleukin-6 inhibitor tocilizumab (TCZ) reduces mortality among hospitalized COVID-19 patients. DESIGN: A systematic review and meta-analysis. METHODS: Systematic review and meta-analysis of randomized controlled trials (RCTs) comparing TCZ vs. placebo/control, for treatment of adults with COVID-19. Primary outcome was 28-30 days all-cause mortality. Search was conducted up to 1 April 2021. Two independent reviewers screened citations, extracted data and assessed risk of bias. Relative risk (RR) with 95% confidence intervals (CI) were pooled. We performed subgroup analysis for patients with critical illness and sensitivity analyses. RESULTS: Eight RCTs were included, assessing 6481 patients with mostly severe non-critical COVID-19 infection. TCZ was associated with a reduction in all-cause 28-30-day mortality compared to placebo/control (RR = 0.89, 95% CI 0.82-0.96). Among the subgroup of critically ill patients no reduced mortality was demonstrated (RR = 0.94, 95% CI 0.74-1.19). No mortality benefit with TCZ was demonstrated in trials that used steroids for >80% of patients. TCZ was associated with significantly reduced risk for mechanical ventilation (MV); for combined endpoint of death or MV and for intensive care unit (ICU) admission. No significant difference in adverse events was demonstrated. Risk of serious superinfection was significantly lower with TCZ (RR = 0.57, 95% CI 0.35-0.93). CONCLUSION: The treatment with TCZ reduces 28-30 days all-cause mortality, ICU admission, superinfections, MV and the combined endpoint of death or MV. Among critically ill patients, and when steroids were used for most patients, no mortality benefit was demonstrated. Additional research should further define sub-groups that would benefit most and preferred timing of administration of TCZ in severe COVID-19.

Denosumab is not associated with risk of malignancy: systematic review and meta-analysis of randomized controlled trials.

The immunomodulatory effects of denosumab have raised concerns for risk of malignancy. This meta-analysis of 25 randomized controlled trials (21,523 patients) shows similar risk of malignancy between denosumab (60 mg every 6 months, up to 48 months) and any comparator. Post-marketing surveillance may detect rare or late-occurring drug effects. Possible increased risk of malignancy in patients treated with denosumab has been concerned due to inhibition of the immune modulator receptor activator of nuclear factor κ-Β ligand (RANKL). We aimed to assess the risk of malignancy associated with denosumab treatment. PubMed and Cochrane Central Register of Controlled Trials were searched up to May 27, 2019 to include all randomized controlled trials of denosumab (60 mg every 6 months) versus any comparator. Trials using higher drug doses for prevention of skeletal-related events were excluded. Data were independently extracted by two reviewers and analyzed using a fixed-effect model to pool risk ratios (RRs) with 95% confidence intervals (CI). Twenty-five trials (21,523 patients) were included. The risk of malignancy was similar between denosumab and other comparators (absolute risk difference 0%, RR 1.08 [95% CI, 0.93-1.24], I2 = 0%). Sensitivity analysis based on adequate allocation concealment showed similar results. The risk of malignancy did not differ between groups in any of the subgroup analyses, including stratification by race, individual comparators, indications for treatment, and longer drug exposure (≥ 24 months, 9 studies). The risk ratio of malignancy-related death was similar between groups. Early concerns about a potential increased risk of malignancy resulting from an immunomodulatory effect of denosumab are not supported by evidence from this meta-analysis of 25 RCTs with drug exposure of up to 48 months. Since RCTs with longer observation for safety outcomes are not expected, post-marketing surveillance will be the main means for detection of rare or late-occurring events.

Comparison of clinical outcomes of influenza A and B at the 2017-2018 influenza season: a cohort study.

Influenza has significant morbidity and mortality. Some experts consider infection with influenza B as milder than that with influenza A. The objective of this study is to evaluate the outcomes of hospitalized patients with laboratory-confirmed influenza A or B in 2017-2018 influenza season. All hospitalized patients between October 2017 and April 2018 with laboratory-confirmed influenza A and B were included. The primary composite outcomes were pneumonia/myocarditis/encephalitis, mechanical ventilation, ICU admission, and 30-day mortality. Secondary outcomes were 30-/90-day mortality, length of hospital stay, and readmission rates. The study included 201 influenza A and 325 influenza B. For the primary composite outcome, no significant difference was demonstrated between influenza A and B. Rates of mortality were similar at 30 and 90 days. Influenza A had higher pneumonia rates and mechanical ventilation. On multivariate analysis, higher Charlson's score, hypoalbuminemia, and vasopressor use were associated with 30-day mortality, while infection with either influenza A or B was not. Influenza A was associated with higher pneumonia and mechanical ventilation rates. However, influenza B resulted with similar 30-day mortality rate as influenza A.

A Case for Expanding Thermochromic Vial Monitor Technology to Insulin and Other Biologics.

Insulin quality and efficacy determine glycemic control, which determines quality of life for people with diabetes. Insulin efficacy is reduced by heat exposure, especially in tropical climates, remote areas, and with improper handling. Insulin doses can be adjusted based on blood glucose monitoring, which may compensate for lack of viability. However, a measured response may be difficult with other biopharmaceuticals. Thermochromic vial monitor technology developed for oral polio vaccines (vaccine vial monitors) is an inexpensive, easily available, visible modality which can be used for insulin and other biopharmaceuticals to detect excessive heat exposure and thus reduced potency at any point in the cold-chain, till the end-users, thus improving patient care. Regulatory authorities must urgently consider the need to impose mandatory use of this technology for all biopharmaceuticals, including insulin, to ensure efficacy till end usage.

Comparison of reporting phase III randomized controlled trials of antibiotic treatment for common bacterial infections in ClinicalTrials.gov and matched publications.

OBJECTIVES: Discrepancies between ClinicalTrials.gov entries and matching publications were previously described in general medicine. We aimed to evaluate the consistency of reporting in trials addressing systemic antibiotic therapy. METHODS: We searched ClinicalTrials.gov for completed phase III trials comparing antibiotic regimens until May 2017. Matched publications were identified in PubMed. Two independent reviewers extracted data and identified inconsistencies. Reporting was assessed among studies started before and after 1 July 2005, when the International Committee of Medical Journal Editors (ICMJE) required mandatory registration as a prerequisite for considering a trial for publication. RESULTS: Matching publications were identified for 75 (70%) of 107 ClinicalTrials.gov entries. Median time from study completion to publication was 26 months (interquartile range 19-42). Primary outcome definition was inconsistent between ClinicalTrials.gov and publications in seven trials (7/72, 10%) and reporting of the primary outcome timeframe was inconsistent in 14 (14/71, 20%). Secondary outcomes definitions were inconsistent in 36 trials (36/66, 55%). Reporting of inclusion criteria and study timeline were inconsistent in 17% (13/65) and 3% (2/65), respectively. Trials started after July 2005 were significantly less likely to have reporting inconsistencies and were published in higher impact factor journals. CONCLUSIONS: We found a lower inconsistency rate of outcome reporting compared with other medical disciplines. Reporting completeness and consistency were significantly better after July 2005. The ICMJE requirement for mandatory registration was associated with significant improvement in reporting quality in infectious diseases trials. Prolonged time lag to publication and missing data from unpublished trials should raise a discussion on current reporting and publishing procedures.

The significance of persistent fever in the treatment of suspected bacterial infections among inpatients: a prospective cohort study.

Antibiotic escalations are frequently guided by fever persistence. Unnecessary antibiotic escalation is associated with resistance induction. We examined whether fever persistence is associated with adverse outcomes among medical inpatients with sepsis. In a single-center prospective cohort study, we included consecutive medical inpatients with suspected or documented bacterial infections. Data were collected on days 0, 2, 4, and 30 days from episode onset. We examined the association between fever persistence at 4 days and 30-day mortality on univariate and multivariate analysis. Inappropriate empirical antibiotic treatment (IAET) was defined for patients with microbiologically documented infections (MDIs). Odds ratios (ORs) are presented with 95% confidence intervals (CIs). A total of 1,621 patients were included. Among patients with MDIs, 38/206 (18.4%) given appropriate empiric therapy had continued fever on day 4, compared to 64/231 (27.7%) of patients receiving IAET, OR 0.59, 95% CI 0.37-0.93. Fever persistence was not associated with mortality after adjustment for other risk factors. Among patients with presumed sepsis who did not have MDIs, persistent fever was significantly associated with 30-day mortality on a multivariate analysis, adjusted OR 2.77 (95% CI 1.78-4.31). Other risk factors for mortality included older age, nosocomial infections, malignancy, dyspnea, shock, decreased albumin, and elevated creatinine. For patients with MDIs, fever persistence for up to 4 days is a marker of IAET, but is not associated with mortality, and should not, in itself, trigger antibiotic escalation. For patients without MDIs, fever persistence should trigger careful re-evaluation, as it is associated with mortality.

Venous thromboembolism prophylaxis with anticoagulation in septic patients: a prospective cohort study.

BACKGROUND: Venous thromboembolism (VTE) is a feared complication during hospitalization. The practice of administering pharmacological prophylaxis is highly endorsed despite failure of studies to show reduction in mortality. AIM: : To determine the benefit of VTE prophylaxis in acutely ill medical patients with sepsis. METHODS: A prospective cohort, with enrollment between January 2010 and April 2011. Patients were detected in four medicine departments at a university-affiliated hospital and followed for 90 days for pre-specified outcomes. We included all septic patients at high VTE risk defined by Padua score ≥ 4. The primary outcome was 30-day mortality. Incidence of pulmonary embolism, deep vein thrombosis or major bleeding episodes at 30 and 90 days, and 90-day mortality were secondary outcomes. RESULTS: A total of 1540 patients were identified, of which 720 (55%) were at high risk for VTE and included. A total of 213 (29.6%) patients received prophylaxis. VTE occurred in 6 control patients and 2 treated (0.9 and 1.2%, respectively, RR 0.79, CI: 0.16-3.95). Major bleeding events occurred in 4 (0.8%) control and 7 (3.3%) treated patients (RR 4.1, CI: 1.24-14.08, P = 0.01). After adjusting for covariates, VTE prophylaxis conferred no 30- or 90-day mortality benefit (OR 1.24, CI: 0.79-1.93 and OR 1.47, CI: 0.99-2.17, respectively). Lack of significant benefit with prophylaxis persisted after propensity-score matching (OR for 30-day mortality 1.01, CI: 0.66-1.55). CONCLUSIONS: In acutely ill inpatients with sepsis, no significant benefit was demonstrated for VTE prophylaxis, with higher rates of bleeding. The risk-benefit ratio of this intervention should be carefully examined.

[18F]FDG-PET/CT for the diagnosis of patients with fever of unknown origin.

BACKGROUND AND AIMS: The diagnosis of patients with fever of unknown origin (FUO) remains a challenging medical problem. We aimed to assess the diagnostic contribution of 18-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET)/computed tomography (CT) for the evaluation of FUO. METHODS: We performed a 4-year retrospective single-center study of all hospitalized patients that underwent FDG-PET/CT for evaluation of FUO. The final diagnosis of the febrile disease was based on clinical, microbiological, radiological and pathological data available at the final follow-up. Predictors for a contributory exam were sought. RESULTS: One hundred and twelve patients underwent FDG-PET/CT for the investigation of FUO in the years 2008-2012 and were included in the study. A final diagnosis was determined in 83 patients (74%) and included: infectious disease in 49 patients (43%), non-infectious inflammatory disease in 17 patients (16%), malignancies in 15 patients (14%), other diagnoses in 2 patients (1.7%), FUO resolved with no diagnosis and no evidence of disease during a 6-month follow-up in 23 patients (20%), and death with fever and with no diagnosis in 6 patients (5%). Seventy-four FDG-PET/CT studies (66%) were considered clinically helpful and contributory to diagnosis (46% positive contributory value and 20.5% contributory to exclusion of diagnosis). PET/CT had a sensitivity of 72.2%, a specificity of 57.5%, a positive predictive value (PPV) of 74.2% and a negative predictive value (NPV) of 53.5%. On multivariable analysis, significant predictors of a positive PET/CT contributory to diagnosis were a short duration of fever and male gender. CONCLUSIONS: PET/CT is an important diagnostic tool for patients with FUO.

Assessment of bias in outcomes reported in trials on pneumonia: a systematic review.

Subjective outcomes may exaggerate intervention effects compared to objectively measured outcomes. We compared effect estimates for clinical failure and all-cause mortality clinical trials of antibiotic treatment for pneumonia. A systematic review of randomized controlled trials assessing adults with pneumonia, comparing different antibiotics, published between 2005 and 2012 was undertaken. We compared the intervention to the control arm. The all-cause mortality in the intention-to-treat population and clinical failure as defined by the study investigators for the primary analyzed population were the primary outcomes examined. Risk ratios (RRs) with 95 % confidence intervals (CIs) were pooled, using a fixed effect model. Meta-regression was used to examine the impact of clinical failure on the mortality effect size. Thirty-six trials were included, of which 30 were industry-sponsored and 30 were non-inferiority trials. There was no difference between the effect on mortality for intervention versus control (RR 1.02, 95 % CI 0.91-1.16) and clinical failure (RR 1.01, 95 % CI 0.93-1.10), without significant heterogeneity in both analyses. In double-blind trials with adequate sequence generation and concealment, there was a significant advantage to the intervention for clinical failure (RR 0.86, 95 % CI 0.76-0.98), but not for mortality (RR 0.96, 95 % CI 0.76-1.21). RRs for clinical failure did not explain the variability in the RRs for mortality significantly, with a meta-regression coefficient of 0.32 (95 % CI -0.21-0.85). In non-inferiority trials of antibiotic treatment for pneumonia, we did not find evidence for bias induced by the use of a subjective outcome overall. The small number of trials without sponsorship precludes an adequate assessment of sponsorship effects.

Postoperative adiponectin levels in pediatric patients undergoing open heart surgery.

BACKGROUND: Adipose tissue is an important endocrine organ that secretes cytokines, including adiponectin, levels of which are negatively correlated with the severity of the inflammatory process. Aim. To assess the time course of adiponectin levels following open heart surgery with cardiopulmonary bypass and its correlation with early postoperative outcomes. MATERIALS AND METHODS: Blood samples were obtained from 24 children undergoing cardiac surgery and analyzed for adiponectin, C-reactive protein, and other inflammatory markers. RESULTS: Baseline adiponectin levels were negatively correlated with patients' preoperative weight and age. Postoperative adiponectin levels decreased compared to baseline (P = 0.01) and correlated negatively with duration of cardiopulmonary bypass (r = -0.438, P = 0.037), length of stay in the pediatric intensive care unit (r = -0.457, P = 0.025), and the inotropic score (r = -0.471, P = 0.02). Adiponectin levels were positively correlated with sVCAM 1 levels; however, there was no correlation between adiponectin levels and sP selectin, tPA, MCP1, and sCD40. CONCLUSIONS: The inflammatory response after open heart surgery with cardiopulmonary bypass is associated with a reduction in adiponectin levels. Prolonged or more complicated surgery induced a more substantial inflammatory process characterized by a significant reduction in adiponectin levels over time and a delayed return to baseline levels.

Cost-benefit of infection control interventions targeting methicillin-resistant Staphylococcus aureus in hospitals: systematic review.

Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) incur significant costs. We aimed to examine the cost and cost-benefit of infection control interventions against MRSA and to examine factors affecting economic estimates. We performed a systematic review of studies assessing infection control interventions aimed at preventing spread of MRSA in hospitals and reporting intervention costs, savings, cost-benefit or cost-effectiveness. We searched PubMed and references of included studies with no language restrictions up to January 2012. We used the Quality of Health Economic Studies tool to assess study quality. We report cost and savings per month in 2011 US$. We calculated the median save/cost ratio and the save-cost difference with interquartile range (IQR) range. We examined the effects of MRSA endemicity, intervention duration and hospital size on results. Thirty-six studies published between 1987 and 2011 fulfilled inclusion criteria. Fifteen of the 18 studies reporting both costs and savings reported a save/cost ratio >1. The median save/cost ratio across all 18 studies was 7.16 (IQR 1.37-16). The median cost across all studies reporting intervention costs (n = 31) was 8648 (IQR 2025-19 170) US$ per month; median savings were 38 751 (IQR 14 206-75 842) US$ per month (23 studies). Higher save/cost ratios were observed in the intermediate to high endemicity setting compared with the low endemicity setting, in hospitals with <500-beds and with interventions of >6 months. Infection control intervention to reduce spread of MRSA in acute-care hospitals showed a favourable cost/benefit ratio. This was true also for high MRSA endemicity settings. Unresolved economic issues include rapid screening using molecular techniques and universal versus targeted screening.