Colistin: new lessons on an old antibiotic

AbstractColistin has been re-introduced into clinical practice for the treatment of carbapenem-resistant Gram-negative bacteria. Studies in the last decade attempted to reconstruct the path that present-day medications undergo prior to clinical use. In this review, we summarize the results of recent clinical studies. Colistin was associated with lower mortality than no effective treatment and higher unadjusted mortality than b-lactams in non-randomized clinical studies. However, it was administered to sicker patients with carabapenem-resistant bacteria. Overall, nephrotoxicity rates were not higher with colistin in these studies, and colistin-induced nephrotoxicity is reversible in most patients. The emergence of colistin resistance has been described in high-use settings. Synergy with carbapenem, rifampin and other antibiotics has been reported in vitro. Randomized controlled trials are ongoing or in planning to assess this and other aspects of colistin use in clinical practice

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

AbstractInfections 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

Higher-order co-occurrences for exploratory point pattern analysis and decision tree clustering on spatial data

Analyzing geographical patterns by collocating events, objects or their attributes has a long history in surveillance and monitoring, and is particularly applied in environmental contexts, such as ecology or epidemiology. The identification of patterns or structures at some scales can be addressed using spatial statistics, particularly marked point processes methodologies. Classification and regression trees are also related to this goal of finding "patterns" by deducing the hierarchy of influence of variables on a dependent outcome. Such variable selection methods have been applied to spatial data, but, often without explicitly acknowledging the spatial dependence. Many methods routinely used in exploratory point pattern analysis are2nd-order statistics, used in a univariate context, though there is also a wide literature on modelling methods for multivariate point pattern processes. This paper proposes an exploratory approach for multivariate spatial data using higher-order statistics built from co-occurrences of events or marks given by the point processes. A spatial entropy measure, derived from these multinomial distributions of co-occurrences at a given order, constitutes the basis of the proposed exploratory methods. © 2010 Elsevier Ltd

Early discontinuation of antibiotics for febrile neutropenia versus continuation until neutropenia resolution

Abstract Background: People with cancer with febrile neutropenia are at risk of severe infections and mortality and are thus treated empirically with broad-spectrum antibiotic therapy. However, the recommended duration of antibiotic therapy differs across guidelines. Objectives: To assess the safety of protocol-guided discontinuation of antibiotics regardless of neutrophil count, compared to continuation of antibiotics until neutropenia resolution in people with cancer with fever and neutropenia, in terms of mortality and morbidity. To assess the emergence of resistant bacteria in people with cancer treated with short courses of antibiotic therapy compared with people with cancer treated until resolution of neutropenia. Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 10) in the Cochrane Library, MEDLINE, Embase, and LILACS up to 1 October 2018. We searched the metaRegister of Controlled Trials and the US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov for ongoing and unpublished trials. We reviewed the references of all identified studies for additional trials and handsearched conference proceedings of international infectious diseases and oncology and haematology conferences. Selection criteria: We included randomised controlled trials (RCTs) that compared a short antibiotic therapy course in which discontinuation of antibiotics was guided by protocols regardless of the neutrophil count to a long course in which antibiotics were continued until neutropenia resolution in people with cancer with febrile neutropenia. The primary outcome was 30-day or end of follow-up all-cause mortality. Data collection and analysis: Two review authors independently reviewed all studies for eligibility, extracted data, and assessed risk of bias for all included trials. We calculated risk ratios (RRs) with 95% confidence intervals (CIs) whenever possible. For dichotomous outcomes with zero events in both arms of the trials, we conducted meta-analysis of risk differences (RDs) as well. For continuous outcomes, we extracted means with standard deviations (SD) from the studies and computed mean difference (MD) and 95% CI. If no substantial clinical heterogeneity was found, trials were pooled using the Mantel-Haenszel fixed-effect model. Main results: We included eight RCTs comprising a total of 662 distinct febrile neutropenia episodes. The studies included adults and children, and had variable design and criteria for discontinuation of antibiotics in both study arms. All included studies but two were performed before the year 2000. All studies included people with cancer with fever of unknown origin and excluded people with microbiological documented infections.We found no significant difference between the short-antibiotic therapy arm and the long-antibiotic therapy arm for all-cause mortality (RR 1.38, 95% CI 0.73 to 2.62; RD 0.02, 95% CI -0.02 to 0.05; low-certainty evidence). We downgraded the certainty of the evidence to low due to imprecision and high risk of selection bias. The number of fever days was significantly lower for people in the short-antibiotic treatment arm compared to the long-antibiotic treatment arm (mean difference -0.64, 95% CI -0.96 to -0.32; I² = 30%). In all studies, total antibiotic days were fewer in the intervention arm by three to seven days compared to the long antibiotic therapy. We found no significant differences in the rates of clinical failure (RR 1.23, 95% CI 0.85 to 1.77; very low-certainty evidence). We downgraded the certainty of the evidence for clinical failure due to variable and inconsistent definitions of clinical failure across studies, possible selection bias, and wide confidence intervals. There was no significant difference in the incidence of bacteraemia occurring after randomisation (RR 1.56, 95% CI 0.91 to 2.66; very low-certainty evidence), while the incidence of any documented infections was significantly higher in the short-antibiotic therapy arm (RR 1.67, 95% CI 1.08 to 2.57). There was no significant difference in the incidence of invasive fungal infections (RR 0.86, 95% CI 0.32 to 2.31) and development of antibiotic resistance (RR 1.49, 95% CI 0.62 to 3.61). The data on hospital stay were too sparse to permit any meaningful conclusions. Authors' conclusions: We could make no strong conclusions on the safety of antibiotic discontinuation before neutropenia resolution among people with cancer with febrile neutropenia based on the existing evidence and its low certainty. Results of microbiological outcomes favouring long antibiotic therapy may be misleading due to lower culture positivity rates under antibiotic therapy and not true differences in infection rates. Well-designed, adequately powered RCTs are required that address this issue in the era of rising antibiotic resistance

Association of vancomycin serum concentrations with efficacy in patients with MRSA infections: a systematic review and meta-analysis

AbstractRecent Infectious Diseases Society of America guidelines for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections recommend maintaining vancomycin trough concentrations of 15–20 mg/L for serious infections. We conducted a systematic review and meta-analysis of all studies assessing the impact of low (<15 mg/L) vs. high (≥15 mg/L) vancomycin trough level on the efficacy of MRSA infections treatment. Four prospective and 12 retrospective studies were included (2003 participants). No significant difference was demonstrated between low and high vancomycin trough level for the outcome of all-cause mortality (odds ratio (OR) 1.07, 95% confidence interval (CI) 0.78–1.46, I2 = 28%). In studies evaluating mainly MRSA pneumonia, there was significantly higher mortality with low vancomycin level (OR 1.78, 95% CI 1.11–2.84). No significant difference was demonstrated in treatment failure rates (OR 1.25, 95% CI 0.88–1.78, I2 = 51%). However, excluding one outlier study from the analysis, treatment failure became significantly higher in patients with low vancomycin trough level (OR 1.46, 95% CI 1.12–1.91, I2 = 16%). Microbiologic failure rates were significantly higher in patients with low vancomycin levels (OR 1.56, 95% CI 1.08–2.26, I2 = 0%). Nephrotoxicity was significantly higher with vancomycin levels of ≥15 mg/L. However, no cases of irreversible renal damage were reported. Current data on the effectiveness of higher vancomycin trough levels in the treatment of MRSA infections are limited to few prospective and mainly retrospective studies. Our findings support the current recommendations for maintaining vancomycin trough levels of ≥15 mg/L in the treatment of severe MRSA infections, although no difference in all-cause mortality was observed

Corticosteroids for pneumonia

BackgroundPneumonia is a common and potentially serious illness. Corticosteroids have been suggested for the treatment of different types of infection, however their role in the treatment of pneumonia remains unclear. This is an update of a review published in 2011.ObjectivesTo assess the efficacy and safety of corticosteroids in the treatment of pneumonia.Search methodsWe searched the Cochrane Acute Respiratory Infections Group's Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS on 3March 2017, together with relevant conference proceedings and references of identified trials. We also searched three trials registers for ongoing and unpublished trials.Selection criteriaWe included randomised controlled trials (RCTs) that assessed systemic corticosteroid therapy, given as adjunct to antibiotic treatment, versus placebo or no corticosteroids for adults and children with pneumonia.Data collection and analysisWe used standard methodological procedures expected by Cochrane. Two review authors independently assessed risk of bias and extracted data. We contacted study authors for additional information. We estimated risk ratios (RR) with 95% confidence intervals (CI) and pooled data using the Mantel-Haenszel fixed-effect model when possible.Main resultsWe included 17 RCTs comprising a total of 2264 participants; 13 RCTs included 1954 adult participants, and four RCTs included 310 children. This update included 12 new studies, excluded one previously included study, and excluded five new trials. One trial awaits classification.All trials limited inclusion to inpatients with community-acquired pneumonia (CAP), with or without healthcare-associated pneumonia (HCAP). We assessed the risk of selection bias and attrition bias as low or unclear overall. We assessed performance bias risk as low for nine trials, unclear for one trial, and high for seven trials. We assessed reporting bias risk as low for three trials and high for the remaining 14 trials.Corticosteroids significantly reduced mortality in adults with severe pneumonia (RR 0.58, 95% CI 0.40 to 0.84; moderate-quality evidence), but not in adults with non-severe pneumonia (RR 0.95, 95% CI 0.45 to 2.00). Early clinical failure rates (defined as death from any cause, radiographic progression, or clinical instability at day 5 to 8) were significantly reduced with corticosteroids in people with severe and non-severe pneumonia (RR 0.32, 95% CI 0.15 to 0.7; and RR 0.68, 95% CI 0.56 to 0.83, respectively; high-quality evidence). Corstocosteroids reduced time to clinical cure, length of hospital and intensive care unit stays, development of respiratory failure or shock not present at pneumonia onset, and rates of pneumonia complications.Among children with bacterial pneumonia, corticosteroids reduced early clinical failure rates (defined as for adults, RR 0.41, 95% CI 0.24 to 0.70; high-quality evidence) based on two small, clinically heterogeneous trials, and reduced time to clinical cure.Hyperglycaemia was significantly more common in adults treated with corticosteroids (RR 1.72, 95% CI 1.38 to 2.14). There were no significant differences between corticosteroid-treated people and controls for other adverse events or secondary infections (RR 1.19, 95% CI 0.73 to 1.93).Authors' conclusionsCorticosteroid therapy reduced mortality and morbidity in adults with severe CAP; the number needed to treat for an additional beneficial outcome was 18 patients (95% CI 12 to 49) to prevent one death. Corticosteroid therapy reduced morbidity, but not mortality, for adults and children with non-severe CAP. Corticosteroid therapy was associated with more adverse events, especially hyperglycaemia, but the harms did not seem to outweigh the benefits

Divine intervention? A Cochrane review on intercessory prayer gone beyond science and reason

We discuss in this commentary a recent Cochrane review of 10 randomised trials aimed at testing the religious belief that praying to a god can help those who are prayed for. The review concluded that the available studies merit additional research. However, the review presented a scientifically unsound mixture of theological and scientific arguments, and two of the included trials that had a large impact on the findings had problems that were not described in the review. The review fails to live up to the high standards required for Cochrane reviews

Retrospective observational study to assess the clinical management and outcomes of hospitalised patients with complicated urinary tract infection in countries with high prevalence of multidrug resistant Gram-negative bacteria (RESCUING)

INTRODUCTION: The emergence of multidrug resistant (MDR) Gram-negative bacteria (GNB), including carbapenemase-producing strains, has become a major therapeutic challenge. These MDR isolates are often involved in complicated urinary tract infection (cUTI), and are associated with poor clinical outcomes. The study has been designed to gain insight into the epidemiology, clinical management, outcome and healthcare cost of patients with cUTI, especially in countries with high prevalence of MDR GNB. METHODS AND ANALYSIS: This multinational and multicentre observational, retrospective study will identify cases from 1 January 2013 to 31 December 2014 in order to collect data on patients with cUTI as a cause of hospital admission, and patients who develop cUTI during their hospital stay. The primary end point will be treatment failure defined as the presence of any of the following criteria: (1) signs or symptoms of cUTI present at diagnosis that have not improved by days 5–7 with appropriate antibiotic therapy, (2) new cUTI-related symptoms that have developed within 30 days of diagnosis, (3) urine culture taken within 30 days of diagnosis, either during or after completion of therapy, that grows ≥104 colony-forming unit/mL of the original pathogen and (4) death irrespective of cause within 30 days of the cUTI diagnosis. SAMPLE SIZE: 1000 patients afford a power of 0.83 (α=0.05) to detect an absolute difference of 10% in the treatment failure rate between MDR bacteria and other pathogens. This should allow for the introduction of about 20 independent risk factors (or their interaction) in a logistic regression model looking at risk factors for failure. ETHICS AND DISSEMINATION: Approval will be sought from all relevant Research Ethics Committees. Publication of this study will be considered as a joint publication by the participating investigator leads, and will follow the recommendations of the International Committee of Medical Journal Editors (ICMJE)

Message to complementary and alternative medicine: evidence is a better friend than power

BACKGROUND: Evidence-based medicine (EBM) is being embraced by an increasing number of practitioners and advocates of complementary and alternative medicine (CAM). A significant constituency within CAM, however, appears to have substantive doubts about EBM and some are expressly hostile. DISCUSSION: Many of the arguments raised against EBM within the CAM community are based on a caricature radically at odds with established, accepted and published principles of EBM practice. Contrary to what has sometimes been argued, EBM is not cookbook medicine that ignores individual needs. Neither does EBM mandate that only proven therapies should be used. Before EBM, decisions on health care tended to be based on tradition, power and influence. Such modes usually act to the disadvantage of marginal groups. CONCLUSION: By placing CAM on an equal footing with conventional medicine - what matters for both is evidence of effectiveness - EBM provides an opportunity for CAM to find an appropriate and just place in health care