Comparable Efficacy and Better Safety of Double β-Lactam Combination Therapy versus β‑Lactam plus Aminoglycoside in Gram-Negative Bacteria in Randomized, Controlled Trials

ABSTRACTThere is a great need for efficacious therapies against Gram-negative bacteria. Double β-lactam combination(s) (DBL) are relatively safe, and preclinical data are promising; however, their clinical role has not been well defined. We conducted a metaanalysis of the clinical and microbiological efficacy of DBL compared to β-lactam plus aminoglycoside combinations (BLAG). PubMed, Embase, ISI Web of Knowledge, and Cochrane Controlled Trials Register database were searched through July 2018. We included randomized controlled clinical trials that compared DBL with BLAG combinations. Clinical response was used as the primary outcome and microbiological response in Gram-negative bacteria as the secondary outcome; sensitivity analyses were performed forPseudomonas aeruginosa,Klebsiellaspp., andEscherichia coli. Heterogeneity and risk of bias were assessed. Safety results were classified by systems and organs. Thirteen studies evaluated 2,771 cases for clinical response and 665 cases for microbiological response in various Gram-negative species. DBL achieved slightly, but not significantly, better clinical response (risk ratio, 1.05; 95% confidence interval [CI], 0.99 to 1.11) and microbiological response in Gram-negatives (risk ratio, 1.11; 95% CI, 0.99 to 1.25) compared with BLAG. Sensitivity analyses by pathogen showed the same trend. No significant heterogeneity across studies was found. DBL was significantly safer than BLAG regarding renal toxicity (6.6% versus 8.8%,P = 0.0338) and ototoxicity (0.7 versus 3.1%,P = 0.0137). Other adverse events were largely comparable. Overall, empirically designed DBL showed comparable clinical and microbiological responses across different Gram-negative species, and were significantly safer than BLAG. Therefore, DBL should be rationally optimized via the latest translational approaches, leveraging mechanistic insights and newer β-lactams for future evaluation in clinical trials.

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Intravenous Colistin Monotherapy versus Combination Therapy against Carbapenem-Resistant Gram-Negative Bacteria Infections: Meta-Analysis of Randomized Controlled Trials

Journal of Clinical Medicine ◽

10.3390/jcm7080208 ◽

2018 ◽

Vol 7 (8) ◽

pp. 208 ◽

Cited By ~ 8

Author(s):

I-Ling Cheng ◽

Yu-Hung Chen ◽

Chih-Cheng Lai ◽

Hung-Jen Tang

Keyword(s):

Combination Therapy ◽

Randomized Controlled Trials ◽

Meta Analysis ◽

Controlled Trials ◽

Gram Negative Bacteria ◽

Gram Negative ◽

Randomized Controlled ◽

Carbapenem Resistant ◽

Significant Difference ◽

All Cause Mortality

This meta-analysis aims to compare intravenous colistin monotherapy and colistin-based combination therapy against carbapenem-resistant gram-negative bacteria (GNB) infections. PubMed, Embase, and Cochrane databases were searched up to July 2018. Only randomized controlled trials (RCTs) evaluating colistin alone and colistin-based combination therapy in the treatment of carbapenem-resistant GNB infections were included. The primary outcome was all-cause mortality. Five RCTs including 791 patients were included. Overall, colistin monotherapy was associated with a risk ratio (RR) of 1.03 (95% confidence interval (CI), 0.89–1.20, I2 = 0%) for all-cause mortality compared with colistin-based combination therapy. The non-significant difference was also detected in infection-related mortality (RR, 1.23, 95% CI, 0.91–1.67, I2 = 0%) and microbiologic response (RR, 0.86, 95% CI, 0.72–1.04, I2 = 62%). In addition, no significant difference was observed in the subgroup analysis—high or low dose, with or without a loading dose, carbapenem-resistant Acinetobacter baumannii infections, and in combination with rifampicin. Finally, colistin monotherapy was not associated with lower nephrotoxicity than colistin combination therapy (RR, 0.98; 95% CI, 0.84–1.21, I2 = 0%). Based on the analysis of the five RCTs, no differences were found between colistin monotherapy and colistin-based combination therapy against carbapenem-resistant GNB infections, especially for A. baumannii infections.

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Selection and Evaluation of Empirical Research in Technology Assessment

International Journal of Technology Assessment in Health Care ◽

10.1017/s0266462300008448 ◽

1989 ◽

Vol 5 (4) ◽

pp. 521-536 ◽

Cited By ~ 11

Author(s):

Thomas C. Chalmers ◽

Peg Hewett ◽

Dinah Reitman ◽

Henry S. Sacks

Keyword(s):

Clinical Trials ◽

Technology Assessment ◽

Scientific Method ◽

Meta Analysis ◽

Sensitivity Analyses ◽

Controlled Trials ◽

Data Bases ◽

Randomized Controlled ◽

Practice Of Medicine ◽

Meta Analyses

Technology assessment involves application of the scientific method to the practice of medicine. Finding all of the assessment reports in a given field is not an easy task. Proper evaluation of those assessments requires the conduct of a prospective experiment in which the sources and results are blinded when the choice is made of papers to exclude and to include, and the process should be carried in duplicate. There are several available data bases for carrying out the search, but because of problems they should be supplemented by reference to the bibliographies of pertinent published articles. Clinical trials included in meta-analyses should be graded by quality and thus facilitate sensitivity analyses. Attention must be paid to the possibility of publication bias. Finally, the advent of meta-analysis makes it desirable to begin randomized controlled trials in areas of uncertainty, even when there is no possibility that individual investigators will encounter enough patients to draw valid conclusions.

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PTSD Treatment Research: An Overview and Evaluation

The Oxford Handbook of Traumatic Stress Disorders, Second Edition ◽

10.1093/oxfordhb/9780190088224.013.31 ◽

2020 ◽

Author(s):

Paula P. Schnurr ◽

Jessica L. Hamblen

Keyword(s):

Clinical Trials ◽

Treatment Outcome ◽

Controlled Trials ◽

Comorbid Conditions ◽

Design Elements ◽

Ptsd Treatment ◽

Design Considerations ◽

Randomized Controlled ◽

Key Concepts ◽

Treatment Research

This chapter provides an overview of key concepts in designing and evaluating clinical trials, with a focus on randomized controlled trials for PTSD. The first section discusses design elements and how they influence the conclusions that can be drawn from a study. Examples from the trauma literature are provided when available to illustrate concepts. The second section explores newer developments in PTSD treatment trials. Specifically, it discusses treatment and design considerations related to common comorbid conditions of PTSD, adapting treatments for low-resource environments and optimizing treatment outcome. The chapter’s goal is to improve the ability of both clinicians and researchers to critically review PTSD clinical trials.

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Enhancing Patient Centricity and Advancing Innovation in Clinical Research with Virtual Randomized Clinical Trials (vRCTs)

Diagnostics ◽

10.3390/diagnostics11020151 ◽

2021 ◽

Vol 11 (2) ◽

pp. 151

Author(s):

Raphael A. Yaakov ◽

Özgür Güler ◽

Tim Mayhugh ◽

Thomas E. Serena

Keyword(s):

Clinical Trials ◽

Randomized Controlled Trials ◽

Randomized Clinical Trials ◽

Regulatory Compliance ◽

Small Sample ◽

Controlled Trials ◽

Holistic View ◽

Health Crisis ◽

Randomized Controlled ◽

Healthcare Needs

The current public health crisis has highlighted the need to accelerate healthcare innovation. Despite unwavering levels of cooperation among academia, industry, and policy makers, it can still take years to bring a life-saving product to market. There are some obvious limitations, including lack of blinding or masking and small sample size, which render the results less applicable to the real world. Traditional randomized controlled trials (RCTs) are lengthy, expensive, and have a low success rate. There is a growing acknowledgement that the current process no longer fully meets the growing healthcare needs. Advances in technology coupled with proliferation of telehealth modalities, sensors, wearable and connected devices have paved the way for a new paradigm. Virtual randomized controlled trials (vRCTs) have the potential to drastically shorten the clinical trial cycle while maximizing patient-centricity, compliance, and recruitment. This new approach can inform clinical trials in real time and with a holistic view of a patient’s health. This paper provides an overview of virtual clinical trials, addressing critical issues, including regulatory compliance, data security, privacy, and ownership.

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The effect of almond intake on lipid profile: a systematic review and meta-analysis of randomized controlled trials

Food & Function ◽

10.1039/d0fo02878a ◽

2021 ◽

Author(s):

Omid Asbaghi ◽

Vihan Moodi ◽

Amir Hadi ◽

Elham Eslampour ◽

Mina Shirinbakhshmasoleh ◽

...

Keyword(s):

Systematic Review ◽

Clinical Trials ◽

Randomized Controlled Trials ◽

Lipid Profile ◽

Meta Analysis ◽

Controlled Trials ◽

Randomized Controlled

A number of clinical trials have examined the effect of almond intake on the lipid profile in recent years; however, the results remain equivocal.

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Iris-Claw Intraocular Lens: Anterior Chamber or Retropupillary Implantation? A Systematic Review and Meta-Analysis

Medicina ◽

10.3390/medicina57080785 ◽

2021 ◽

Vol 57 (8) ◽

pp. 785

Author(s):

I-Chia Liang ◽

Yun-Hsiang Chang ◽

Adrián Hernández Hernández Martínez ◽

Chi-Feng Hung

Keyword(s):

Anterior Chamber ◽

Intraocular Lens ◽

Meta Analysis ◽

Secondary Outcome ◽

Controlled Trials ◽

Cochrane Central Register ◽

Randomized Controlled ◽

Cell Counts ◽

Iop Elevation ◽

Iris Claw

Background and Objectives: Iris-claw intraocular lens (ICIOL) could be implanted in the anterior chamber (AC) or retropupillary (RP) in eyes lacking capsular and/or zonular support. Several studies have focused on comparing the efficacy and complications of these two techniques and we designed this research to review the published literatures. Materials and Methods: Peer-reviewed studies were collected through network databases (PubMed, Scopus, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov) and analyzed. The primary outcome was the standardized mean differences (SMDs) of pre- and post-operative corrected distant visual acuity (CDVA). The secondary outcome was the SMDs of pre- and post-operative intraocular pressure (IOP), endothelial cell counts (ECC), and the odds ratios (ORs) of post-operative IOP elevation and cystoid macular edema (CME). Comprehensive Meta-Analysis software was utilized to conduct statistical analysis. Results: Six studies (one randomized controlled trial and five retrospective case series) were relevant and included a total of 516 eyes (255 and 261 eyes in the AC ICIOL and RP ICIOL groups, respectively). The quantitative analysis showed no significant differences in CDVA (SMD: 0.164, 95% confidence interval (CI): −0.171 to 0.500), ECC (SMD: −0.011, 95% CI: −0.195 to 0.173), and IOP elevation events (OR: 0.797, 95% CI: 0.459 to 1.383). Lesser IOP reduction (SMD: 0.257, 95%CI: 0.023 to 0.490) and a relative increase in the incidence of CME (OR:2.315, 95% CI: 0.950 to 5.637) were observed in the AC ICIOL group compared with RP ICIOL group. Conclusions: Our meta-analysis indicated that AC and RP ICIOL seem to have equivalent visual outcomes. RP ICIOL may perform slightly better with more IOP reduction and lesser CME. More randomized controlled trials, which have higher patient participation and more outcomes are needed to confirm our conclusions.

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Mindfulness-based and acceptance-based programmes in the treatment of obsessive–compulsive disorder: a study protocol for a systematic review and meta-analysis

BMJ Open ◽

10.1136/bmjopen-2021-050329 ◽

2021 ◽

Vol 11 (6) ◽

pp. e050329

Author(s):

Johannes Julian Bürkle ◽

Johannes Caspar Fendel ◽

Stefan Schmidt

Keyword(s):

Systematic Review ◽

Depressive Symptoms ◽

Obsessive Compulsive Disorder ◽

Meta Analysis ◽

Sensitivity Analyses ◽

Secondary Outcome ◽

Controlled Trials ◽

Obsessive Compulsive ◽

Compulsive Disorder

IntroductionCognitive–behavioural therapy (CBT) with exposure and response prevention is the recommended standard for the treatment of obsessive–compulsive disorder (OCD). However, a high proportion of patients refuse this treatment, do not respond or relapse shortly after treatment. Growing evidence suggests that mindfulness-based and acceptance-based programmes (MABPs) are an effective option for the treatment of OCD. This systematic review and meta-analysis will examine the effectiveness of MABPs in treating OCD. We also aimed to explore potential moderators of the programmes’ effectiveness.Methods and analysisWe will systematically search MEDLINE, Embase, PsycINFO, PSYINDEX, Web of Science, CINAHL and Cochrane Register of Controlled Trials (no language restrictions) for studies that evaluate the effect of MABPs on patients with OCD. We will conduct backward and forward citation searches of included studies and relevant reviews and contact corresponding authors. The primary outcome will be pre-post intervention change in symptom severity. A secondary outcome will be change in depressive symptoms. Two reviewers will independently screen the records, extract the data and rate the methodological quality of the studies. We will include both controlled and uncontrolled trials. Randomised controlled trials will be meta-analysed, separately assessing between-group effects. A second meta-analysis will assess the within-group effect of all eligible studies. We will explore moderators and sources of heterogeneity such as the specific programme, study design, changes in depressive symptoms, hours of guided treatment, control condition and prior therapy (eg, CBT) using metaregression and subgroup analyses. We will perform sensitivity analyses using follow-up data. A narrative synthesis will also be pursued. We will use the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to assess the quality of the evidence.Ethics and disseminationEthical approval is not required. Results will be published in peer-reviewed journals and presented at international conferences.

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Improved Antimicrobial Activities of Synthetic-Hybrid Bacteriocins Designed from Enterocin E50-52 and Pediocin PA-1

Applied and Environmental Microbiology ◽

10.1128/aem.03477-14 ◽

2014 ◽

Vol 81 (5) ◽

pp. 1661-1667 ◽

Cited By ~ 20

Author(s):

Santosh Kumar Tiwari ◽

Katia Sutyak Noll ◽

Veronica L. Cavera ◽

Michael L. Chikindas

Keyword(s):

Micrococcus Luteus ◽

Electrical Potential ◽

Gram Negative Bacteria ◽

Additional Advantage ◽

Gram Negative ◽

Content Type ◽

Intracellular Atp ◽

Hybrid Peptides ◽

C Terminus ◽

N Terminus

ABSTRACTTwo hybrid bacteriocins, enterocin E50-52/pediocin PA-1 (EP) and pediocin PA-1/enterocin E50-52 (PE), were designed by combining the N terminus of enterocin E50-52 and the C terminus of pediocin PA-1 and by combining the C terminus of pediocin PA-1 and the N terminus of enterocin E50-52, respectively. Both hybrid bacteriocins showed reduced MICs compared to those of their natural counterparts. The MICs of hybrid PE and EP were 64- and 32-fold lower, respectively, than the MIC of pediocin PA-1 and 8- and 4-fold lower, respectively, than the MIC of enterocin E50-52. In this study, the effect of hybrid as well as wild-type (WT) bacteriocins on the transmembrane electrical potential (ΔΨ) and their ability to induce the efflux of intracellular ATP were investigated. Enterocin E50-52, pediocin PA-1, and hybrid bacteriocin PE were able to dissipate ΔΨ, but EP was unable to deplete this component. Both hybrid bacteriocins caused a loss of the intracellular concentration of ATP. EP, however, caused a faster efflux than PE and enterocin E50-52. Enterocin E50-52 and hybrids PE and EP were active against the Gram-positive and Gram-negative bacteria tested, such asMicrococcus luteus,Salmonella entericaserovar Enteritidis 20E1090, andEscherichia coliO157:H7. The hybrid bacteriocins designed and described herein are antimicrobial peptides with MICs lower those of their natural counterparts. Both hybrid peptides induce the loss of intracellular ATP and are capable of inhibiting Gram-negative bacteria, and PE dissipates the electrical potential. In this study, the MIC of hybrid bacteriocin PE decreased 64-fold compared to the MIC of its natural peptide counterpart, pediocin PA-1. Inhibition of Gram-negative pathogens confers an additional advantage for the application of these peptides in therapeutics.

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A High-Throughput Approach To Identify Compounds That Impair Envelope Integrity in Escherichia coli

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00537-16 ◽

2016 ◽

Vol 60 (10) ◽

pp. 5995-6002 ◽

Cited By ~ 7

Author(s):

Kristin R. Baker ◽

Bimal Jana ◽

Henrik Franzyk ◽

Luca Guardabassi

Keyword(s):

Escherichia Coli ◽

High Throughput ◽

High Throughput Screening ◽

Gram Negative Bacteria ◽

Chromogenic Substrate ◽

Intrinsic Resistance ◽

Gram Negative ◽

Content Type ◽

E Coli ◽

Screening Platform

ABSTRACTThe envelope of Gram-negative bacteria constitutes an impenetrable barrier to numerous classes of antimicrobials. This intrinsic resistance, coupled with acquired multidrug resistance, has drastically limited the treatment options against Gram-negative pathogens. The aim of the present study was to develop and validate an assay for identifying compounds that increase envelope permeability, thereby conferring antimicrobial susceptibility by weakening of the cell envelope barrier in Gram-negative bacteria. A high-throughput whole-cell screening platform was developed to measureEscherichia colienvelope permeability to a β-galactosidase chromogenic substrate. The signal produced by cytoplasmic β-galactosidase-dependent cleavage of the chromogenic substrate was used to determine the degree of envelope permeabilization. The assay was optimized by using known envelope-permeabilizing compounds andE. coligene deletion mutants with impaired envelope integrity. As a proof of concept, a compound library comprising 36 peptides and 45 peptidomimetics was screened, leading to identification of two peptides that substantially increased envelope permeability. Compound 79 reduced significantly (from 8- to 125-fold) the MICs of erythromycin, fusidic acid, novobiocin and rifampin and displayed synergy (fractional inhibitory concentration index, <0.2) with these antibiotics by checkerboard assays in two genetically distinctE. colistrains, including the high-risk multidrug-resistant, CTX-M-15-producing sequence type 131 clone. Notably, in the presence of 0.25 μM of this peptide, both strains were susceptible to rifampin according to the resistance breakpoints (R> 0.5 μg/ml) for Gram-positive bacterial pathogens. The high-throughput screening platform developed in this study can be applied to accelerate the discovery of antimicrobial helper drug candidates and targets that enhance the delivery of existing antibiotics by impairing envelope integrity in Gram-negative bacteria.

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Trends in randomized controlled trials in ENT: a 30-year review

The Journal of Laryngology & Otology ◽

10.1017/s0022215100138101 ◽

1997 ◽

Vol 111 (7) ◽

pp. 611-613 ◽

Cited By ~ 9

Author(s):

K. W. Ah-See ◽

N. C. Molony ◽

A. G. D. Maran

Keyword(s):

Clinical Trials ◽

Clinical Practice ◽

Randomized Controlled Trials ◽

Gold Standard ◽

Controlled Trials ◽

Evidence Based ◽

Controlled Clinical Trials ◽

Medline Search ◽

Randomized Controlled Clinical Trials ◽

Randomized Controlled

AbstractThere is a growth in the demand for clinical practice to be evidence based. Recent years have seen a rise in the number of randomized controlled clinical trials (RCTS). Such trials while acknowledged as the gold standard for evidence can be difficult to perform in surgical specialities. We have recently identified a low proportion of RCTS in the otolaryngology literature. Our aim was to identify any trend in the number of published RCTS within the ENT literature over a 30-year period and to identify which areas of our speciality lend themselves to this form of study design. A Medline search of 10 prominent journals published between 1966 and 1995 was performed. Two hundred and ninety-six RCTS were identified. Only five were published before 1980. Two hundred (71 per cent) of RCTS were in the areas of otology and rhinology. An encouraging trend is seen in RCTS within ENT literature.

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