High-dose rifamycins in the treatment of TB: a systematic review and meta-analysis.

BACKGROUND: There is growing interest in using high-dose rifamycin (HDR) regimens in TB treatment, but the safety and efficacy of HDR regimens remain uncertain. We performed a systematic review and meta-analysis comparing HDR to standard-dose rifamycin (SDR) regimens. METHODS: We searched MEDLINE, Embase, CENTRAL, Cochrane Database of Systematic Reviews and clinicaltrials.gov for prospective studies comparing daily therapy with HDRs to SDRs. Rifamycins included rifampicin, rifapentine and rifabutin. Our primary outcome was the rate of severe adverse events (SAEs), with secondary outcomes of death, all adverse events, SAE by organ and efficacy outcomes of 2-month culture conversion and relapse. This study was prospectively registered in the International Prospective Register of Systematic Reviews (CRD42020142519). RESULTS: We identified 9057 articles and included 13 studies with 6168 participants contributing 7930 person-years (PY) of follow-up (HDR: 3535 participants, 4387 PY; SDR: 2633 participants, 3543 PY). We found no significant difference in the pooled incidence rate ratio (IRR) of SAE between HDR and SDR (IRR 1.00, 95% CI 0.82 to 1.23, I 2=41%). There was no significant difference when analysis was limited to SAE possibly, probably or likely medication-related (IRR 1.07, 95% CI 0.82 to 1.41, I 2=0%); studies with low risk of bias (IRR 0.98, 95% CI 0.79 to 1.20, I 2=44%); or studies using rifampicin (IRR 1.00, 95% CI 0. 0.75-1.32, I 2=38%). No significant differences were noted in pooled outcomes of death, 2-month culture conversion and relapse. CONCLUSIONS: HDRs were not associated with a significant difference in SAEs, 2-month culture conversion or death. Further studies are required to identify specific groups who may benefit from HDR.

Patient Characteristics and Outcomes of Outpatient Parenteral Antimicrobial Therapy: A Retrospective Study.

Outpatient parenteral antimicrobial therapy (OPAT) is a safe and effective alternative to hospitalization for many patients with infectious diseases. The objective of this study was to describe the OPAT experience at a Canadian tertiary academic centre in the absence of a formal OPAT program. This was achieved through a retrospective chart review of OPAT patients discharged from Sunnybrook Health Sciences Centre within a one-year period. Between June 2012 and May 2013, 104 patients (median age 63 years) were discharged home with parenteral antimicrobials. The most commonly treated syndromes included surgical site infections (33%), osteoarticular infections (28%), and bacteremia (21%). The most frequently prescribed antimicrobials were ceftriaxone (21%) and cefazolin (20%). Only 56% of the patients received follow-up care from an infectious diseases specialist. In the 60 days following discharge, 43% of the patients returned to the emergency department, while 26% required readmission. Forty-eight percent of the return visits were due to infection relapse or treatment failure, and 23% could be attributed to OPAT-related complications. These results suggest that many OPAT patients have unplanned health care encounters because of issues related to their infection or treatment, and the creation of a formal OPAT clinic may help improve outcomes.

External Validation of the BACES Score in Canadian Patients With Nontuberculous Mycobacterial Pulmonary Disease.

BACKGROUND: The clinical course of nontuberculous mycobacterial pulmonary disease (NTM-PD) can be variable and difficult to predict. Recently, the BACES score was developed as a tool to predict all-cause mortality in patients with NTM-PD. This score is calculated based on five patient characteristics (BMI, age, cavity, erythrocyte sedimentation rate, and sex), and higher scores portend worse prognosis. Although the BACES score has been validated in a cohort of South Korean patients, it has not yet been validated in other settings or ethnic groups. RESEARCH QUESTION: How well does the BACES mortality score perform in a cohort of Canadian patients with NTM-PD? STUDY DESIGN AND METHODS: We performed a single-center retrospective chart review. Patients who were seen between July 2003 and June 2021 were eligible for inclusion if they met guideline-based diagnostic criteria for NTM-PD and were excluded if any component of the BACES score was missing. To assess the model's discriminatory performance, we compared Kaplan-Meier curves between risk groups and calculated Harrell's C index. To assess calibration, we used a graphical calibration curve. RESULTS: The cohort included 435 patients with a median follow-up of 5.8 years. The median age was 64 years and 74% were female. Based on the BACES scores, patients were classified into three risk groups: low, moderate, or high. Survival curves showed clear separation of the risk groups. Harrell's C index was 0.733 in the study cohort, indicating moderate to good discriminatory performance, although this was lower than the value reported in the derivation cohort (0.812). The graphical calibration curve showed a tendency of the BACES model to underpredict mortality. INTERPRETATION: The BACES model was evaluated in a multicultural cohort of Canadian patients and demonstrated good discriminatory performance but suboptimal calibration, which may be due to population differences, the use of dichotomized variables in model construction, or both.

The comprehensive antibiotic resistance database.

The field of antibiotic drug discovery and the monitoring of new antibiotic resistance elements have yet to fully exploit the power of the genome revolution. Despite the fact that the first genomes sequenced of free living organisms were those of bacteria, there have been few specialized bioinformatic tools developed to mine the growing amount of genomic data associated with pathogens. In particular, there are few tools to study the genetics and genomics of antibiotic resistance and how it impacts bacterial populations, ecology, and the clinic. We have initiated development of such tools in the form of the Comprehensive Antibiotic Research Database (CARD; http://arpcard.mcmaster.ca). The CARD integrates disparate molecular and sequence data, provides a unique organizing principle in the form of the Antibiotic Resistance Ontology (ARO), and can quickly identify putative antibiotic resistance genes in new unannotated genome sequences. This unique platform provides an informatic tool that bridges antibiotic resistance concerns in health care, agriculture, and the environment.

The Other Nontuberculous Mycobacteria: Clinical Aspects of Lung Disease Caused by Less Common Slowly Growing Nontuberculous Mycobacteria Species.

Slowly growing nontuberculous mycobacteria (NTM) comprise a diverse group of environmental organisms, many of which are important human pathogens. The most common and well-known member of this group is Mycobacterium avium, the leading cause of nontuberculous mycobacterial pulmonary disease (NTM-PD) globally. This review focuses on the less common, but notable, species of slowly growing NTM with respect to lung disease. To prepare this article, literature searches were performed using each species name as the key word. Society guidelines were consulted, and relevant articles also were identified through the reference lists of key articles. The specific organisms highlighted include Mycobacterium kansasii, Mycobacterium xenopi, Mycobacterium malmoense, Mycobacterium simiae, and Mycobacterium szulgai. Although these organisms are closely related, they have distinct epidemiologic features and behavior as pathogens. Therefore, the diagnosis and management of NTM-PD require a nuanced approach that takes into consideration the unique characteristics of each species. There is limited evidence to inform the optimal treatment of NTM-PD. Antimicrobial therapy is often challenging because of the presence of drug resistance and few antibiotic options. Regimen selection should generally be guided by drug susceptibility testing, although the correlation between clinical outcomes and in vitro susceptibility thresholds has not been defined for most species.

Treatment of the Less Common Nontuberculous Mycobacterial Pulmonary Disease.

Nontuberculous mycobacterial pulmonary disease caused by the less common nontuberculous mycobacteria have distinct features depending on the species. Diagnostic evaluation follows the established criteria for all nontuberculous mycobacteria, but with certain qualifications given species-specific and regional differences in pathogenicity. Clinicians should first institute nonpharmacologic management and evaluate clinical, radiologic, and microbiologic factors in the decision regarding antimycobacterial therapy. Treatment is challenging, and evidence-based recommendations are limited for most species. Drug susceptibility testing is used to help with regimen selection; however, this approach is imperfect given the uncertain correlation between in vitro activity and clinical response for most drugs.

Long-term macrolide therapy for chronic obstructive pulmonary disease: a population-based time series analysis.

BACKGROUND: Macrolides are recommended as an adjunctive treatment for patients with moderate to severe chronic obstructive pulmonary disease (COPD) who experience recurrent exacerbations. The objective of this study was to examine temporal trends in the provision of long-term macrolide therapy, specifically before and after publication of the landmark MACRO trial in August 2011 showing efficacy of macrolides for this indication. METHODS: We performed an interrupted time series analysis using population-level health administrative data. The study cohort consisted of all Ontario residents who had COPD, were using at least 1 long-acting inhaler, and were aged 65 years and older between Apr. 1, 2004, and Mar. 31, 2018. We compared the baseline characteristics of eligible patients before and after publication of the MACRO trial. Our primary outcome was overall prevalence of long-term macrolide therapy; secondary outcomes were incidence of COPD-related hospitalizations, emergency department visits and outpatient exacerbations requiring high-dose steroids in each quarter. We performed an interrupted time series analysis to assess for changes in the incidence of macrolide prophylaxis by quarter-year over the study period. RESULTS: The rate of long-term macrolide use increased from 0.8 per 1000 people in 2004 to 13.8 per 1000 people in 2018 (in the severe COPD group, the rate increased from 1.3 to 32.3 per 1000 people). The interrupted time series analysis showed that, before 2011, the prevalence of macrolide prophylaxis increased at a rate of 0.44 (95% confidence interval [CI] 0.39-0.50) per 1000 people per year; after 2011, the rate of increase grew by 1.18 (95% CI 1.07-1.29) per 1000 people to 1.63 (95% CI 1.56-1.69) per 1000 people per year. The seasonal pattern of COPD-related health care visits remained stable over the study period, and there was no detectable reduction in hospitalizations or emergency department visits at the population level. INTERPRETATION: In the past decade, there has been a significant rise in the use of long-term macrolide therapy for patients with COPD. As this practice becomes increasingly common, it will be important to monitor its potential benefits on COPD exacerbations but also its potential effects on adverse events and antimicrobial resistance patterns.

Assessing the utilization and impact of a newly established outpatient parenteral antimicrobial therapy (OPAT) program.

Background: Outpatient parenteral antimicrobial therapy (OPAT) is a safe and effective alternative to hospitalization for many patients with infectious disease. The objective of this study was to describe the experience with a newly established formal OPAT program at a Canadian academic centre. Methods: We conducted a retrospective cohort study including all patients referred to the OPAT clinic between July 2016 and June 2017 and a contemporary cohort of patients who received home parenteral therapy without clinic referral. A quasi-experimental design was used to assess the impact of the clinic on patient outcomes compared with a pre-intervention cohort of patients from 2012 to 2013. Results: Between July 2016 and June 2017, 334 patients were referred to the OPAT clinic; 33% of the patients visited the emergency department (ED), and 21% required readmission within 60 days. Compared with the clinic patients, urinary tract infection diagnoses were more common among the 39 contemporary patients who were treated with home parenteral antibiotics without OPAT clinic referral (51% versus 4%, respectively; p < 0.001) and treatment durations were shorter (median 10 days versus 42 days; p < 0.001). Compared with a pre-intervention cohort, OPAT clinic implementation was associated with a trend toward decreased ED visits (33% versus 43%; p = 0.07). On multivariable analysis, this translated to an overall adjusted odds ratio of 0.64 (95% CI 0.40 to 1.04, p = 0.07) for readmission and ED visits. Conclusions: The OPAT clinic served a high volume of patients in its first year of operation and may be helpful in reducing unfavourable patient outcomes.

Historique: L'antibiothérapie parentérale ambulatoire (APA) remplace l'hospitalisation de manière sécuritaire et efficace pour bien des patients atteints d'une maladie infectieuse. La présente étude visait à décrire l'expérience d'un nouveau programme officiel d'APA dans un centre universitaire canadien. Méthodologie: Les auteurs ont procédé à une étude de cohorte rétrospective incluant tous les patients orientés vers une clinique d'APA entre juillet 2016 et juin 2017 et une cohorte de patients qui, pendant la même période, ont reçu un traitement parentéral à domicile sans être orientés en clinique. Ils ont utilisé une méthodologie quasi-expérimentale pour évaluer les répercussions du suivi en clinique sur les patients par rapport à une cohorte de patients avant l'intervention, entre 2012 et 2013. Résultats: Entre juillet 2016 et juin 2017, 334 patients ont été orientés vers la clinique d'APA; 33 % ont consulté à l'urgence et 21 % ont dû être réhospitalisés dans les 60 jours. Les diagnostics d'infection urinaire étaient plus courants chez les 39 patients recevant une antibiothérapie parentérale à domicile sans être dirigés vers une clinique d'APA que dans la cohorte suivie en clinique (51 % par rapport à 4 %, respectivement; p < 0,001) et la durée du traitement était plus courte (médiane de dix jours par rapport à 42 jours; p < 0,001). Par rapport à la cohorte observée avant l'intervention, le suivi en clinique d'APA était associé à une tendance vers une diminution des consultations à l'urgence (33 % par rapport à 43 %; p = 0,07). À l'analyse multivariable, ces résultats se traduisaient par un rapport de cotes rajusté global de 0,64 (IC à 95 %, 0,40 à 1,04, p = 0,07) pour la réhospitalisation et les consultations à l'urgence. Conclusions: La clinique d'APA a accueilli un fort volume de patients pendant sa première année de fonctionnement et peut contribuer à réduire les résultats cliniques défavorables chez les patients.

Chemoradiotherapy regimens for locoregionally advanced nasopharyngeal carcinoma: A Bayesian network meta-analysis.

BACKGROUND: Concurrent chemoradiotherapy followed by adjuvant chemotherapy (CRT-A) is often the regimen of choice in locoregionally advanced nasopharyngeal carcinoma (NPC). Many alternative regimens have been reported in the literature, however, it is unknown how effective these regimens are compared to each other due to the lack of direct comparisons. Our objective was to perform a network meta-analysis (NMA) to determine the relative survival benefits of these treatments for locoregionally advanced NPC. METHODS: We performed a systematic review following the Cochrane methodology, using MEDLINE, EMBASE and CENTRAL to identify all randomised controlled trials (RCTs) that compared different chemoradiotherapy regimens for locoregionally advanced NPC. Overall survival (OS) was the primary outcome of interest, and hazard ratios (HRs) were extracted using the Parmar method. Bayesian NMAs with random effects were conducted using WinBUGS. RESULTS: Twenty-five RCTs (5576 patients) were included in this review. All together, these trials compared seven different regimens: radiotherapy (RT), concurrent chemoradiotherapy (CRT), neoadjuvant followed by CRT (N-CRT), CRT-A, RT-A, N-RT and N-RT-A. All regimens that contained CRT performed significantly better than RT. CRT-A did not improve survival compared to CRT alone (0.98; 95% credible regions: 0.71-1.34). For N-CRT versus CRT, the HR was 1.03 (0.69-1.47). When CRT-A was compared against N-CRT, the resulting HR was 0.96 (0.64-1.48). CONCLUSIONS: Adjuvant chemotherapy does not appear to improve survival following CRT. The efficacies of CRT, CRT-A and N-CRT all appeared to be similar. Further studies are warranted to determine the value of additional chemotherapy phases in specific patient subgroups.

A Systematic Review and Network Meta-Analysis of Biologic Agents in the First Line Setting for Advanced Colorectal Cancer.

BACKGROUND: Epithelial growth factor receptor inhibitors (EGFRis) and bevacizumab (BEV) are used in combination with chemotherapy for the treatment of metastatic colorectal cancer (mCRC). However, few randomized controlled trials (RCTs) have directly compared their relative efficacy on progression-free survival (PFS) and overall survival (OS). METHODS: We conducted a systematic review of first-line RCTs comparing (1) EGFRis vs. BEV, with chemotherapy in both arms (2) EGFRis + chemotherapy vs. chemotherapy alone, or (3) BEV + chemotherapy vs. chemotherapy alone, using Cochrane methodology. Data on and PFS and OS were extracted using the Parmar method. Pairwise meta-analyses and Bayesian network meta-analyses (NMA) were conducted to estimate the direct, indirect and combined PFS and OS hazard ratios (HRs) comparing EGFRis to BEV. RESULTS: Seventeen RCTs contained extractable data for quantitative analysis. Combining direct and indirect data using an NMA did not show a statistical difference between EGFRis versus BEV (PFS HR = 1.11 (95% CR: 0.92-1.36) and OS HR = 0.91 (95% CR: 0.75-1.09)). Direct meta-analysis (3 RCTs), indirect (14 RCTs) and combined (17 RCTs) NMA of PFS HRs were concordant and did not show a difference between EGFRis and BEV. Meta-analysis of OS using direct evidence, largely influenced by one trial, showed an improvement with EGFRis therapy (HR = 0.79 (95% CR: 0.65-0.98)), while indirect and combined NMA of OS did not show a difference between EGFRis and BEV Successive inclusions of trials over time in the combined NMA did not show superiority of EGFRis over BEV. CONCLUSIONS: Our findings did not support OS or PFS benefits of EGFRis over BEV in first-line mCRC.

Self resistance to the atypical cationic antimicrobial peptide edeine of Brevibacillus brevis Vm4 by the N-acetyltransferase EdeQ.

Edeines are atypical cationic peptides produced by Brevibacillus brevis Vm4 with broad-spectrum antimicrobial activity. These linear nonribosomal peptides bind to the 30S ribosomal subunit and block t-RNA binding to the P-site. To identify the mechanism of high-level self-resistance in the producing organism, the B. brevis Vm4 genome was sequenced and the edeine biosynthetic cluster discovered. A potential edeine-modifying enzyme, EdeQ, showed similarity to spermidine N-acetyltransferases. EdeQ was purified and shown to convert edeine to N-acetyledeine, which is inactive against cells in vivo and against cell-free extracts. Unexpectedly, tandem mass spectroscopy and nuclear magnetic resonance demonstrate that N-acylation occurs on the free amine of the internal diaminopropionic acid rather than the N-terminal spermidine polyamine. Acetylation of edeine by EdeQ abolishes its ability to inhibit translation, thus conferring resistance to the antibiotic in the producing organism.