Impact of amoxicillin-clavulanate followed by autologous fecal microbiota transplantation on fecal microbiome structure and metabolic potential

The spread of multidrug resistance among pathogenic organisms threatens the efficacy of antimicrobial treatment options. The human gut serves as a reservoir for many drug-resistant organisms and their resistance genes, and perturbation of the gut microbiome by antimicrobial exposure can open metabolic niches to resistant pathogens. Once established in the gut, antimicrobial-resistant bacteria can persist even after antimicrobial exposure ceases. Strategies to prevent multidrug-resistant organism (MDRO) infections are scarce, but autologous fecal microbiota transplantation (autoFMT) may limit gastrointestinal MDRO expansion. AutoFMT involves banking one’s feces during a healthy state for later use in restoring gut microbiota following perturbation. This pilot study evaluated the effect of amoxicillin-clavulanic acid (Amox-Clav) exposure and autoFMT on gastrointestinal microbiome taxonomic composition, resistance gene content, and metabolic capacity. Importantly, we found that metabolic capacity was perturbed even in cases where gross phylogeny remained unchanged and that autoFMT was safe and well tolerated.Strategies to prevent multidrug-resistant organism (MDRO) infections are scarce, but autologous fecal microbiota transplantation (autoFMT) may limit gastrointestinal MDRO expansion. AutoFMT involves banking one’s feces during a healthy state for later use in restoring gut microbiota following perturbation. This pilot study evaluated the effect of autoFMT on gastrointestinal microbiome taxonomic composition, resistance gene content, and metabolic capacity after exposure to amoxicillin-clavulanic acid (Amox-Clav). Ten healthy participants were enrolled. All received 5 days of Amox-Clav. Half were randomized to autoFMT, derived from stool collected pre-antimicrobial exposure, by enema, and half to saline enema. Participants submitted stool samples pre- and post-Amox-Clav and enema and during a 90-day follow-up period. Shotgun metagenomic sequencing revealed taxonomic composition, resistance gene content, and metabolic capacity. Amox-Clav significantly altered gut taxonomic composition in all participants (n = 10, P  0.05, compared to enrollment). Alterations to microbial metabolic capacity occurred following antimicrobial exposure even in participants without substantial taxonomic disruption, potentially creating open niches for pathogen colonization. Our findings suggest that metabolic potential is an important consideration for complete assessment of antimicrobial impact on the microbiome. AutoFMT was well tolerated and may have contributed to phylogenetic recovery. (This study has been registered at ClinicalTrials.gov under identifier NCT02046525.

Microbiota restoration reduces antibiotic-resistant bacteria gut colonization in patients with recurrent Clostridioides difficile infection from the open-label PUNCH CD study

BACKGROUND: Once antibiotic-resistant bacteria become established within the gut microbiota, they can cause infections in the host and be transmitted to other people and the environment. Currently, there are no effective modalities for decreasing or preventing colonization by antibiotic-resistant bacteria. Intestinal microbiota restoration can prevent Clostridioides difficile infection (CDI) recurrences. Another potential application of microbiota restoration is suppression of non-C. difficile multidrug-resistant bacteria and overall decrease in the abundance of antibiotic resistance genes (the resistome) within the gut microbiota. This study characterizes the effects of RBX2660, a microbiota-based investigational therapeutic, on the composition and abundance of the gut microbiota and resistome, as well as multidrug-resistant organism carriage, after delivery to patients suffering from recurrent CDI. METHODS: An open-label, multi-center clinical trial in 11 centers in the USA for the safety and efficacy of RBX2660 on recurrent CDI was conducted. Fecal specimens from 29 of these subjects with recurrent CDI who received either one (N = 16) or two doses of RBX2660 (N = 13) were analyzed secondarily. Stool samples were collected prior to and at intervals up to 6 months post-therapy and analyzed in three ways: (1) 16S rRNA gene sequencing for microbiota taxonomic composition, (2) whole metagenome shotgun sequencing for functional pathways and antibiotic resistome content, and (3) selective and differential bacterial culturing followed by isolate genome sequencing to longitudinally track multidrug-resistant organisms. RESULTS: Successful prevention of CDI recurrence with RBX2660 correlated with taxonomic convergence of patient microbiota to the donor microbiota as measured by weighted UniFrac distance. RBX2660 dramatically reduced the abundance of antibiotic-resistant Enterobacteriaceae in the 2 months after administration. Fecal antibiotic resistance gene carriage decreased in direct relationship to the degree to which donor microbiota engrafted. CONCLUSIONS: Microbiota-based therapeutics reduce resistance gene abundance and resistant organisms in the recipient gut microbiome. This approach could potentially reduce the risk of infections caused by resistant organisms within the patient and the transfer of resistance genes or pathogens to others. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01925417 ; registered on August 19, 2013

Postdischarge antibiotic use for prophylaxis following spinal fusion

OBJECTIVE: Despite recommendations to discontinue prophylactic antibiotics after incision closure or \u3c24 hours after surgery, prophylactic antibiotics are continued after discharge by some clinicians. The objective of this study was to determine the prevalence and factors associated with postdischarge prophylactic antibiotic use after spinal fusion. DESIGN: Multicenter retrospective cohort study. PATIENTS: This study included patients aged ≥18 years undergoing spinal fusion or refusion between July 2011 and June 2015 at 3 sites. Patients with an infection during the surgical admission were excluded. METHODS: Prophylactic antibiotics were identified at discharge. Factors associated with postdischarge prophylactic antibiotic use were identified using hierarchical generalized linear models. RESULTS: In total, 8,652 spinal fusion admissions were included. Antibiotics were prescribed at discharge in 289 admissions (3.3%). The most commonly prescribed antibiotics were trimethoprim/sulfamethoxazole (22.1%), cephalexin (18.8%), and ciprofloxacin (17.1%). Adjusted for study site, significant factors associated with prophylactic discharge antibiotics included American Society of Anesthesiologists (ASA) class ≥3 (odds ratio [OR], 1.31; 95% CI, 1.00-1.70), lymphoma (OR, 2.57; 95% CI, 1.11-5.98), solid tumor (OR, 3.63; 95% CI, 1.62-8.14), morbid obesity (OR, 1.64; 95% CI, 1.09-2.47), paralysis (OR, 2.38; 95% CI, 1.30-4.37), hematoma/seroma (OR, 2.93; 95% CI, 1.17-7.33), thoracic surgery (OR, 1.39; 95% CI, 1.01-1.93), longer length of stay, and intraoperative antibiotics. CONCLUSIONS: Postdischarge prophylactic antibiotics were uncommon after spinal fusion. Patient and perioperative factors were associated with continuation of prophylactic antibiotics after hospital discharge

Surgeon choice in the use of postdischarge antibiotics for prophylaxis following mastectomy with and without breast reconstruction

Multiple guidelines recommend discontinuation of prophylactic antibiotics \u3c24 hours after surgery. In a multicenter, retrospective cohort of 2,954 mastectomy patients ± immediate breast reconstruction, we found that utilization of prophylactic postdischarge antibiotics varied dramatically at the surgeon level among general surgeons and was virtually universal among plastic surgeons

Impact of investigational microbiota therapeutic RBX2660 on the gut microbiome and resistome revealed by a placebo-controlled clinical trial

BACKGROUND: Intestinal microbiota restoration can be achieved by complementing a subject\u27s perturbed microbiota with that of a healthy donor. Recurrent Clostridioides difficile infection (rCDI) is one key application of such treatment. Another emerging application of interest is reducing antibiotic-resistant genes (ARGs) and organisms (AROs). In this study, we investigated fecal specimens from a multicenter, randomized, double-blind, placebo-controlled phase 2b study of microbiota-based investigational drug RBX2660. Patients were administered either placebo, 1 dose of RBX2660 and 1 placebo, or 2 doses of RBX2660 via enema and longitudinally tracked for changes in their microbiome and antibiotic resistome. RESULTS: All patients exhibited significant recovery of gut microbiome diversity and a decrease of ARG relative abundance during the first 7 days post-treatment. However, the microbiome and resistome shifts toward average configurations from unperturbed individuals were more significant and longer-lasting in RBX2660 recipients compared to placebo. We quantified microbiome and resistome modification by RBX2660 using a novel transplantation index metric. We identified taxonomic and metabolic features distinguishing the baseline microbiome of non-transplanted patients and taxa specifically enriched during the process of transplantation. We elucidated the correlation between resistome and taxonomic transplantations and post-treatment dynamics of patient-specific and RBX2660-specific ARGs. Whole genome sequencing of AROs cultured from RBX2660 product and patient samples indicate ARO eradication in patients via RBX2660 administration, but also, to a lesser extent, introduction of RBX2660-derived AROs. CONCLUSIONS: Through shotgun metagenomic sequencing, we elucidated the effects of RBX2660 in the microbiome and resistome. Antibiotic discontinuation alone resulted in significant recovery of gut microbial diversity and reduced ARG relative abundance, but RBX2660 administration more rapidly and completely changed the composition of patients\u27 microbiome, resistome, and ARO colonization by transplanting RBX2660 microbiota into the recipients. Although ARGs and AROs were transmitted through RBX2660, the resistome post-RBX2660 more closely resembled that of the administered product-a proxy for the donor-than an antibiotic perturbed state. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02299570 . Registered 19 November 2014 Video Abstract

Postdischarge prophylactic antibiotics following mastectomy with and without breast reconstruction

BACKGROUND: Prophylactic antibiotics are commonly prescribed at discharge for mastectomy, despite guidelines recommending against this practice. We investigated factors associated with postdischarge prophylactic antibiotic use after mastectomy with and without immediate reconstruction and the impact on surgical-site infection (SSI). STUDY DESIGN: We studied a cohort of women aged 18-64 years undergoing mastectomy between January 1, 2010, and June 30, 2015, using the MarketScan commercial database. Patients with nonsurgical perioperative infections were excluded. Postdischarge oral antibiotics were identified from outpatient drug claims. SSI was defined using International Classification of Diseases, Ninth Edition, Clinical Modification (ICD-9-CM) diagnosis codes. Generalized linear models were used to determine factors associated with postdischarge prophylactic antibiotic use and SSI. RESULTS: The cohort included 38,793 procedures; 24,818 (64%) with immediate reconstruction. Prophylactic antibiotics were prescribed after discharge after 2,688 mastectomy-only procedures (19.2%) and 17,807 mastectomies with immediate reconstruction (71.8%). The 90-day incidence of SSI was 3.5% after mastectomy only and 8.8% after mastectomy with immediate reconstruction. Antibiotics with anti-methicillin-sensitive Staphylococcus aureus (MSSA) activity were associated with decreased SSI risk after mastectomy only (adjusted relative risk [aRR], 0.74; 95% confidence interval [CI], 0.55-0.99) and mastectomy with immediate reconstruction (aRR, 0.80; 95% CI, 0.73-0.88), respectively. The numbers needed to treat to prevent 1 additional SSI were 107 and 48, respectively. CONCLUSIONS: Postdischarge prophylactic antibiotics were common after mastectomy. Anti-MSSA antibiotics were associated with decreased risk of SSI for patients who had mastectomy only and those who had mastectomy with immediate reconstruction. The high numbers needed to treat suggest that potential benefits of postdischarge antibiotics should be weighed against potential harms associated with antibiotic overuse

Utilizing the focused conversation method in qualitative public health research: a team-based approach

Abstract Background Qualitative research studies are becoming increasingly necessary to understand the complex challenges in the healthcare setting. Successfully integrating interdisciplinary teams of investigators can be challenging, as investigators inherently view data through their disciplinary lens. Thus, new methods, such as focused conservation, are needed to facilitate qualitative data analysis by interdisciplinary teams. The purpose of this manuscript is to provide a clear description of how we implemented the focused conversation method to facilitate an organized data-driven discussion that responded to our study objectives and ensured participation of our interdisciplinary team. The focused conversation method has not, to our knowledge, been utilized for this purpose to date. Methods To better understand the experience of healthcare personnel (HCP) during preparations for the 2014–2015 Ebola Virus Disease (EVD) outbreak, we interviewed HCP who participated in decision making about EVD preparations and training of workers in the use of enhanced personal protective equipment ensembles in the metropolitan Chicagoland area of Illinois to attain a priori research objectives. We identified a systematic method – the focused conversation method – that enabled our interdisciplinary team to interactively contribute to the framing, analysis and interpretation of the data that would enable us to focus on our research objectives. Results The focused conversation developed to support our a priori research objective about the training of HCP in preparations included objective, reflective, interpretive and decisional questions. These questions grounded the conversation in the data, while leveraging discipline-specific lenses and professional experience in the analysis and interpretation. Insights from the conversation were reviewed later against interview transcripts to ensure validity. The conversation identified areas for future research directions and deficiencies in the interview instrument. Conclusions The focused conversation is an efficient, organized method for analysis of qualitative data by an interdisciplinary team

A randomized controlled trial of Lactobacillus rhamnosus GG on antimicrobial-resistant organism colonization

OBJECTIVE: Alteration of the colonic microbiota following antimicrobial exposure allows colonization by antimicrobial-resistant organisms (AROs). Ingestion of a probiotic, such as Lactobacillus rhamnosus GG (LGG), could prevent colonization or infection with AROs by promoting healthy colonic microbiota. The purpose of this trial was to determine the effect of LGG administration on ARO colonization in hospitalized patients receiving antibiotics. DESIGN: Prospective, double-blinded, randomized controlled trial of LGG versus placebo among patients receiving broad-spectrum antibiotics. SETTING: Tertiary care center. PATIENTS: In total, 88 inpatients receiving broad-spectrum antibiotics were enrolled. INTERVENTION: Patients were randomized to receive 1 capsule containing 1×1010 cells of LGG twice daily (n = 44) or placebo (n = 44), stratified by ward type. Stool or rectal-swab specimens were collected for culture at enrollment, during admission, and at discharge. Using selective media, specimens were cultured for Clostridioides difficile, vancomycin-resistant Enterococcus spp (VRE), and antibiotic-resistant gram-negative bacteria. The primary outcome was any ARO acquisition. Secondary outcomes included loss of any ARO if colonized at enrollment, and acquisition or loss of individual ARO. RESULTS: ARO colonization prevalence at study enrollment was similar (LGG 39% vs placebo 39%). We detected no difference in any ARO acquisition (LGG 30% vs placebo 33%; OR,1.19; 95% CI, 0.38-3.75) nor for any individual ARO acquisition. There was no difference in the loss of any ARO (LGG 18% vs placebo 24%; OR, 1.44; 95% CI, 0.27-7.68) nor for any individual ARO. CONCLUSION: LGG administration neither prevented acquisition of ARO nor accelerated loss of ARO colonization

Effect of meteorological factors and geographic location on methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci colonization in the US.

BACKGROUND:Little is known about the effect of meteorological conditions and geographical location on bacterial colonization rates particularly of antibiotic-resistant Gram-positive bacteria. We aimed to evaluate the effect of season, meteorological factors, and geographic location on methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) colonization. METHODS:The prospective cohort included all adults admitted to 20 geographically-dispersed ICUs across the US from September 1, 2011 to October 4, 2012. Nasal and perianal swabs were collected at admission and tested for MRSA and VRE colonization respectively. Poisson regression models using monthly aggregated colonization counts as the outcome and mean temperature, relative humidity, total precipitation, season, and/or latitude as predictors were constructed for each pathogen. RESULTS:A total of 24,704 ICU-admitted patients were tested for MRSA and 24,468 for VRE. On admission, 10% of patients were colonized with MRSA and 12% with VRE. For MRSA and VRE, a 10% increase in relative humidity was associated with approximately a 9% increase in prevalence rate. Southerly latitudes in the US were associated with higher MRSA colonization, while northerly latitudes were associated with higher VRE colonization. In contrast to MRSA, the association between VRE colonization and latitude was observed only after adjusting for relative humidity, which demonstrates how this effect is highly driven by this meteorological factor. CONCLUSIONS:To our knowledge, we are the first to study the effect of meteorological factors and geographical location/latitude on MRSA and VRE colonization in adults. Increasing humidity was associated with greater MRSA and VRE colonization. Southerly latitudes in the US were associated with greater MRSA and less VRE. The effect of these factors on MRSA and VRE rates has the potential not only to inform patient management and treatment, but also infection prevention interventions

Modeling Spread of KPC-Producing Bacteria in Long-Term Acute Care Hospitals in the Chicago Region, USA

OBJECTIVE. Prevalence of bla(KPC)-encoding Enterobacteriaceae (KPC) in Chicago long-term acute care hospitals (LTACHs) rose rapidly after the first recognition in 2007. We studied the epidemiology and transmission capacity of KPC in LTACHs and the effect of patient cohorting. METHODS. Data were available from 4 Chicago LTACHs from June 2012 to June 2013 during a period of bundled interventions. These consisted of screening for KPC rectal carriage, daily chlorhexidine bathing, medical staff education, and 3 cohort strategies: a pure cohort (all KPC-positive patients on 1 floor), single rooms for KPC-positive patients, and a mixed cohort (all KPC-positive patients on 1 floor, supplemented with KPC-negative patients). A data-augmented Markov chain Monte Carlo (MCMC) method was used to model the transmission process. RESULTS. Average prevalence of KPC colonization was 29.3%. On admission, 18% of patients were colonized; the sensitivity of the screening process was 81%. The per admission reproduction number was 0.40. The number of acquisitions per 1,000 patient days was lowest in LTACHs with a pure cohort ward or single rooms for colonized patients compared with mixed-cohort wards, but 95% credible intervals overlapped. CONCLUSIONS. Prevalence of KPC in LTACHs is high, primarily due to high admission prevalence and the resultant impact of high colonization pressure on cross transmission. In this setting, with an intervention in place, patient-to-patient transmission is insufficient to maintain endemicity. Inclusion of a pure cohort or single rooms for KPC-positive patients in an intervention bundle seemed to limit transmission compared to use of a mixed cohort