Gram stain-guided antibiotic choice: a GRACEful method to safely restrict overuse of broad-spectrum antibiotic agents.
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SUBMITTER: Yoshimura J
PROVIDER: S-EPMC6295032 | biostudies-literature | 2018 Dec
REPOSITORIES: biostudies-literature
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Gram stain-guided antibiotic choice: a GRACEful method to safely restrict overuse of broad-spectrum antibiotic agents.
Yoshimura Jumpei J Yamakawa Kazuma K Kinoshita Takahiro T Fujimi Satoshi S
Critical care (London, England) 20181214 1
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Project description:BackgroundOptimising the use of antibiotic agents is a pressing challenge to overcoming the rapid emergence and spread of multidrug-resistant pathogens in intensive care units (ICUs). Although Gram staining may possibly provide immediate information for predicting pathogenic bacteria, Gram stain-guided initial antibiotic treatment is not well established in the ICU setting. We planned the GRam stain-guided Antibiotics ChoicE for Ventilator-Associated Pneumonia (GRACE-VAP) trial to investigate whether Gram staining can safely restrict the use of broad-spectrum antibiotics in patients with ventilator-associated pneumonia (VAP), which is one of the most common hospital-acquired infections in ICUs.Methods/designThe GRACE-VAP trial is a multicentre, randomised, open-label parallel-group trial to assess the non-inferiority of Gram stain-guided initial antibiotic treatment to guidelines-based initial antibiotic treatment for the primary endpoint of clinical response rate in patients with VAP. Secondary endpoints include the coverage rates of initial antibiotic therapies, the selected rates of anti-pseudomonal agents and anti-methicillin-resistant Staphylococcus aureus (anti-MRSA) agents as initial antibiotic therapies, 28-day all-cause mortality, ICU-free days, ventilator-free days and adverse events. Patients are randomly assigned to receive Gram stain-guided treatment or guidelines-based treatment at a ratio of 1:1. In the Gram stain group, results of Gram staining of endotracheal aspirate are used to guide the selection of antibiotics. In the guidelines group, the combination of an anti-pseudomonal agent and an anti-MRSA agent is administered. A total sample size of 200 was estimated to provide a power of 80% with a one-sided alpha level of 2.5% and a non-inferiority margin of 20%, considering 10% non-evaluable patients.DiscussionThe GRACE-VAP trial is expected to reveal whether Gram staining can reduce the use of broad-spectrum antibiotics without impairing patient outcomes and thereby provide evidence for an antibiotic selection strategy in patients with VAP.Trial registrationClinicaltrials.gov, NCT03506113 . Registered on 29 March 2018. University Hospital Medical Information Network, UMIN000031933. Registered on 26 March 2018.
| S-EPMC6225572 | biostudies-literature
Project description:ImportanceGram staining should provide immediate information for detecting causative pathogens. However, the effect of Gram staining on restricting the initial antibiotic choice has not been investigated in intensive care units (ICUs).ObjectiveTo compare the clinical response to Gram stain-guided restrictive antibiotic therapy vs guideline-based broad-spectrum antibiotic treatment in patients with ventilator-associated pneumonia (VAP).Design, setting, and participantsThis multicenter, open-label, noninferiority randomized clinical trial (Gram Stain-Guided Antibiotics Choice for VAP) was conducted in the ICUs of 12 tertiary referral hospitals in Japan from April 1, 2018, through May 31, 2020. Patients aged 15 years or older with a VAP diagnosis and a modified Clinical Pulmonary Infection Score of 5 or higher were included. The primary analysis was based on the per-protocol analysis population.InterventionsPatients were randomized to Gram stain-guided antibiotic therapy or guideline-based antibiotic therapy (based on the 2016 Infectious Disease Society of America and American Thoracic Society clinical practice guidelines for VAP).Main outcomes and measuresThe primary outcome was the clinical response rate; clinical response was defined as completion of antibiotic therapy within 14 days, improvement or lack of progression of baseline radiographic findings, resolution of signs and symptoms of pneumonia, and lack of antibiotic agent readministration, with a noninferiority margin of 20%. Secondary outcomes were the proportions of antipseudomonal agents and anti-methicillin-resistant Staphylococcus aureus (MRSA) agents as initial antibiotic therapies; 28-day mortality, ICU-free days, ventilator-free days; and adverse events.ResultsIn total, 206 patients (median [IQR] age, 69 [54-78] years; 141 men [68.4%]) were randomized to the Gram stain-guided group (n = 103) or guideline-based group (n = 103). Clinical response occurred in 79 patients (76.7%) in the Gram stain-guided group and 74 patients (71.8%) in the guideline-based group (risk difference, 0.05; 95% CI, -0.07 to 0.17; P < .001 for noninferiority). Reduced use of antipseudomonal agents (30.1%; 95% CI, 21.5%-39.9%; P < .001) and anti-MRSA agents (38.8%; 95% CI, 29.4%-48.9%; P < .001) was observed in the Gram stain-guided group vs guideline-based group. The 28-day cumulative incidence of mortality was 13.6% (n = 14) in the Gram stain-guided group vs 17.5% (n = 18) in the guideline-based group (P = .39). Escalation of antibiotics according to culture results was performed in 7 patients (6.8%) in the Gram stain-guided group and 1 patient (1.0%) in the guideline-based group (P = .03). There were no significant differences between the groups in ICU-free days, ventilator-free days, and adverse events.Conclusions and relevanceResults of this trial showed that Gram stain-guided treatment was noninferior to guideline-based treatment and significantly reduced the use of broad-spectrum antibiotics in patients with VAP. Gram staining can potentially ameliorate the multidrug-resistant organisms in the critical care setting.Trial registrationClinicalTrials.gov Identifier: NCT03506113.
| S-EPMC8994124 | biostudies-literature
Project description:Magnetizing: Bacteria are often classified into gram-positive and gram-negative strains by staining with crystal violet (CV). The described bioorthogonal modification of CV with trans-cyclooctene (TCO) can be used to render gram-positive bacteria magnetic with tetrazine-functionalized magnetic nanoparticles (MNP-Tz). This method allows class-specific automated magnetic detection and magnetic separation.
| S-EPMC3496380 | biostudies-literature
Project description:The global incidence of drug-resistant Gram-negative bacillary infections has been increasing, and there is a dire need to develop novel strategies to overcome this problem. Intrinsic resistance in Gram-negative bacteria, such as their protective outer membrane and constitutively overexpressed efflux pumps, is a major survival weapon that renders them refractory to current antibiotics. Several potential avenues to overcome this problem have been at the heart of antibiotic drug discovery in the past few decades. We review some of these strategies, with emphasis on antibiotic hybrids either as stand-alone antibacterial agents or as adjuvants that potentiate a primary antibiotic in Gram-negative bacteria. Antibiotic hybrid is defined in this review as a synthetic construct of two or more pharmacophores belonging to an established agent known to elicit a desired antimicrobial effect. The concepts, advances, and challenges of antibiotic hybrids are elaborated in this article. Moreover, we discuss several antibiotic hybrids that were or are in clinical evaluation. Mechanistic insights into how tobramycin-based antibiotic hybrids are able to potentiate legacy antibiotics in multidrug-resistant Gram-negative bacilli are also highlighted. Antibiotic hybrids indeed have a promising future as a therapeutic strategy to overcome drug resistance in Gram-negative pathogens and/or expand the usefulness of our current antibiotic arsenal.
| S-EPMC5967690 | biostudies-literature
Project description:IntroductionAntibiotic overuse drives antibiotic resistance. The optimal duration of antibiotic therapy for Gram-negative bacteraemia (GNB), a common community and hospital-associated infection, remains unknown and unstudied via randomised controlled trials (RCTs).Methods and analysisThis investigator-initiated, multicentre, non-inferiority, informatics-based point-of-care RCT will randomly assign adult hospitalised patients receiving microbiologically efficacious antibiotic(s) for GNB to (1) 14 days of antibiotic therapy, (2) 7 days of therapy or (3) an individualised duration determined by clinical response and 75% reduction in peak C reactive protein (CRP) values. The randomisation will occur in equal proportions (1:1:1) on day 5 (±1) of efficacious antibiotic therapy as determined by antibiogram; patients, their physicians and study investigators will be blind to treatment duration allocation until the day of antibiotic discontinuation. Immunosuppressed patients and those with GNB due to complicated infections (endocarditis, osteomyelitis, etc) and/or non-fermenting bacilli (Acinetobacter spp, Burkholderia spp, Pseudomonas spp) Brucella spp, Fusobacterium spp or polymicrobial growth with Gram-positive organisms will be ineligible. The primary outcome is incidence of clinical failure at day 30; secondary outcomes include clinical failure, all-cause mortality and incidence of Clostridiumdifficile infection in the 90-day study period. An interim safety analysis will be performed after the first 150 patients have been followed for ≤30 days. Given a chosen margin of 10%, the required sample size to determine non-inferiority is roughly 500 patients. Analyses will be performed on both intention-to-treat and per-protocol populations.Ethics and disseminationEthics approval was obtained from the cantonal ethics committees of all three participating sites. Results of the main trial and each of the secondary endpoints will be submitted for publication in a peer-reviewed journal.Trial registration numberThis trial is registered at www.clinicaltrials.gov (NCT03101072; pre-results).
| S-EPMC5541592 | biostudies-literature
Project description:There is an urgent need to develop novel antibiotic agents that can combat emerging drug resistance. Herein, we report the design and investigation of a class of short dimeric antimicrobial lipo-α/sulfono-γ-AA hybrid peptides. Some of these peptides exhibit potent and broad-spectrum antimicrobial activity toward both clinically related Gram-positive and Gram-negative bacteria. The TEM study suggests that these hybrid peptides can compromise bacterial membranes and lead to bacterial death. Membrane depolarization and fluorescence microscopy studies also indicate that the mechanism of action is analogous to host-defense peptides (HDPs). Furthermore, the lead compound shows the ability to effectively inhibit biofilms formed from MRSA and E. coli. Further development of the short dimeric lipo-α/sulfono-γ-AA hybrid peptides may lead to a new generation of antimicrobial biomaterials to combat drug resistance.
| S-EPMC8903075 | biostudies-literature
Project description:Tetronomycin (1), first isolated from a cultured broth of Streptomyces sp. by Juslen et al. in 1974, is a polycyclic polyether compound. However, the biological activity of 1 has not been thoroughly examined. In this study, we found that 1 exhibits more potent antibacterial activity than two well-known antibacterial drugs (vancomycin and linezolid) and is effective against several drug-resistant clinical isolates including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococci. Furthermore, we reassigned the 13C NMR spectra of 1 and performed a preliminary structure-activity relationship study of 1 to synthesize a chemical probe for target identification, which implied different targets based on its ionophore activity.
| S-EPMC10061530 | biostudies-literature
Project description:ObjectiveTo understand public attitudes about and recommendations to address antibiotic overuse by employing public deliberation (a method for eliciting informed input on value-laden issues).Data sources/study settingParticipants in 24 Community Deliberation groups (CD; n = 263), four Citizens' Panel groups (CP; n = 96), and a control group (n = 348). Data were collected in 2012 in four U.S.LocationsStudy designUsing mixed methods, we analyzed quantitative and qualitative data from a randomized control trial.Data collection/extraction methodsUsing pre/postdeliberation surveys, we compared CD and CP participant attitude changes regarding antibiotic use to the control group. We analyzed deliberation transcripts using qualitative techniques to provide context for survey results.Principal findingsCompared to control group participants, CD and CP participants had a larger postdeliberation shift in attitudes toward support of government limits on when doctors can prescribe antibiotics. Participants described unawareness about antibiotic overuse and called for education. When discussing prescription limits, participants debated tensions between preserving patient/doctor autonomy and protecting society from antibiotic-related harms. Participants saw patient, physician, and government roles in antibiotic stewardship policies/programs.ConclusionWhen informed about individual and social consequences of antibiotic overuse, patients may be more receptive to antibiotic prescription limits. Community-physician-government partnerships are needed to create solutions.
| S-EPMC6863223 | biostudies-literature
Project description:Antimicrobial stewardship programs focus on reducing overuse of broad-spectrum antibiotics (BSAs), primarily through interventions to change prescribing behavior. This study aims to identify multi-level influences on BSA overuse across diverse high and low income, and public and private, healthcare contexts. Semi-structured interviews were conducted with 46 prescribers from hospitals in the UK, Sri Lanka, and South Africa, including public and private providers. Interviews explored decision making about prescribing BSAs, drivers of the use of BSAs, and benefits of BSAs to various stakeholders, and were analyzed using a constant comparative approach. Analysis identified drivers of BSA overuse at the individual, social and structural levels. Structural drivers of overuse varied significantly across contexts and included: system-level factors generating tensions with stewardship goals; limited material resources within hospitals; and patient poverty, lack of infrastructure and resources in local communities. Antimicrobial stewardship needs to encompass efforts to reduce the reliance on BSAs as a solution to context-specific structural conditions.
| S-EPMC7835907 | biostudies-literature
Project description:BackgroundThe role of changes in gut microflora on upper gastrointestinal (UGI) perforations is not known. We conducted a retrospective case-control study to examine the relationship between antibiotic exposure-a proxy for microbiome modulation-and UGI perforations in a national sample.MethodsWe queried a 5% random sample of Medicare (2009-2013) to identify patients ≥ 65 years old hospitalized with UGI (stomach or small intestine) perforations using International Classification of Diseases diagnosis codes. Cases with UGI perforations were matched with 4 controls, each based on age and sex. Exposure to outpatient antibiotics (0-30, 31-60, 61-90 days) prior to case patients' index hospitalization admission data was determined with Part D claims. Univariate and multivariable regression analyses were performed to evaluate the effect of antibiotic exposure on UGI perforation.ResultsOverall, 504 cases and 2016 matched controls were identified. Compared to controls, more cases had antibiotic exposure 0-30 days (19% vs. 3%, p < 0.001) and 31-60 days (5% vs. 2%, p < 0.001) prior to admission. In adjusted analyses, antibiotic exposure 0-30 days prior to admission was associated with 6.8 increased odds of an UGI perforation (95% CI 4.8, 9.8); 31-60 days was associated with 1.9 increased odds (95% CI 1.1, 3.3); and 61-90 days was associated with 3.7 increased odds (95% CI 2.0, 6.9).ConclusionsRecent outpatient antibiotic use, in particular in the preceding 30 days, is associated with UGI perforation among Medicare beneficiaries. Exposure to antibiotics, one of the most modifiable determinants of the microbiome, should be minimized in the outpatient setting.
| S-EPMC8133306 | biostudies-literature