Search

Background: Epidemiologic studies have shown decreasing vancomycin susceptibility among clinical Clostridioides difficile isolates, but the impact on patient outcomes is unknown. We hypothesized that reduced vancomycin susceptibility would be associated with decreased rates of sustained clinical response (SCR)., Methods: This multicenter cohort study included adults with C. difficile infection (CDI) treated with oral vancomycin between 2016 and 2021. Clostridioides difficile isolates underwent agar dilution vancomycin susceptibility testing, ribotyping, and Sanger sequencing of the vancomycin resistance vanR gene. Reduced susceptibility was defined as vancomycin minimum inhibitory concentration (MIC) >2 μg/mL. The primary outcome was 30-day SCR; secondary outcomes were 14-day initial cure, 30-day recurrence, and 30-day mortality. Exploratory analysis assessed the association between the VanR Thr115Ala polymorphism, susceptibility, and outcomes., Results: A high proportion (34% [102/300]) of C. difficile isolates exhibited reduced vancomycin susceptibility (range, 0.5-16 μg/mL; MIC50/90 = 2/4 μg/mL). Ribotype 027 accounted for the highest proportion (77.4% [41/53]) of isolates with reduced vancomycin susceptibility. Overall, 83% (249) of patients achieved 30-day SCR. Reduced vancomycin susceptibility was associated with lower rates of 30-day SCR (76% [78/102]) than vancomycin-susceptible strains (86% [171/198]; P = .031). A significantly lower rate of 14-day initial cure was also observed among individuals infected with strains with reduced vancomycin susceptibility (89% vs 96%; P = .04). Reduced susceptibility remained an independent predictor of 30-day SCR in multivariable modeling (odds ratio, 0.52 [95% confidence interval, .28-.97]; P = .04)., Conclusions: Reduced vancomycin susceptibility in C. difficile was associated with decreased odds of 30-day SCR and lower 14-day initial cure rates in the studied patient cohort., Competing Interests: Potential conflicts of interest. K. W. G. and A. J. G.-L. have received research funding from Merck. K. W. G. has received additional research funding from Acurx Pharmaceuticals. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Exposure to antibiotics predisposes to dysbiosis and Clostridioides difficile infection (CDI) that can be severe, recurrent (rCDI), and life-threatening. Nonselective drugs that treat CDI and perpetuate dysbiosis are associated with rCDI, in part due to loss of microbiome-derived secondary bile acid (SBA) production. Ridinilazole is a highly selective drug designed to treat CDI and prevent rCDI., Methods: In this phase 3 superiority trial, adults with CDI, confirmed with a stool toxin test, were randomized to receive 10 days of ridinilazole (200 mg twice daily) or vancomycin (125 mg 4 times daily). The primary endpoint was sustained clinical response (SCR), defined as clinical response and no rCDI through 30 days after end of treatment. Secondary endpoints included rCDI and change in relative abundance of SBAs., Results: Ridinilazole and vancomycin achieved an SCR rate of 73% versus 70.7%, respectively, a treatment difference of 2.2% (95% CI: -4.2%, 8.6%). Ridinilazole resulted in a 53% reduction in recurrence compared with vancomycin (8.1% vs 17.3%; 95% CI: -14.1%, -4.5%; P = .0002). Subgroup analyses revealed consistent ridinilazole benefit for reduction in rCDI across subgroups. Ridinilazole preserved microbiota diversity, increased SBAs, and did not increase the resistome. Conversely, vancomycin worsened CDI-associated dysbiosis, decreased SBAs, increased Proteobacteria abundance (∼3.5-fold), and increased the resistome., Conclusions: Although ridinilazole did not meet superiority in SCR, ridinilazole greatly reduced rCDI and preserved microbiome diversity and SBAs compared with vancomycin. These findings suggest that treatment of CDI with ridinilazole results in an earlier recovery of gut microbiome health. Clinical Trials Registration.Ri-CoDIFy 1 and 2: NCT03595553 and NCT03595566., Competing Interests: Potential conflicts of interest. K. W. G. received grants paid to his institution from Acurx, Paratek, Cidara, Therapeutics, and Seres Health. P. C. O. received faculty grant/research support from Merck, Sharp and Dohme, Deinove Pharmaceuticals, Summit Pharmaceuticals, Melinta Pharmaceuticals, the National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases (NIAID), Kieberg Foundation, and Napo Pharmaceutical; is a consultant to Napo Pharmaceutical, Ferring Pharmaceutical, Summit Pharmaceutical, SNIPR Biome Company, Haleon, and SNIPR; received payment for speaking from Colegio Mexicano de Medicina Interna; participated on a Scientific Advisory Board for Napo Pharmaceuticals; and has stock or stock options from Moderna, Pfizer, Haleon, Biontech, GSK, Novavax, AstraZeneca, Beam, and Johnson & Johnson. T. L. attended advisory board meetings for Summit, Inc, and received payments for the conduct of clinical trials for Seres Therapeutics, Finch Therapeutics, and Rebiotix/Ferring. E. D. and D. J. were employees of Summit, Inc, and owned stock options in Summit Therapeutics (parent company) at the time of manuscript submission. J. G. M. is a part-time employee and owns stock options in Summit, Inc. E. R. D. has received grants paid to his institution from Theriva Biologics and Ferring and consulting fees from Pfizer, Merck, Seres, Abbott, AstraZeneca, Summit, GSK, and Ferring. M. W. has received consulting fees from AiCuris, Bayer, Crestone, Da Volterra, Deinove, EnteroBiotix, The European Tissue Symposium, Ferring, GSK, Menarini, Merck, Nestlé, Paion, Paratek, Pfizer, Phico Therapeutics, Qpex Biopharma, Seres, Surface Skins, Summit, Tillotts, Vaxxilon/Idorsia, and Vedanta; lecture fees from GSK, Merck, Pfizer, Seres, and Tillotts; and grant support from Almirall, Da Volterra, EnteroBiotix, GSK, Merck, MicroPharm, Nabriva, Paratek, Pfizer, Seres, Summit, The European Tissue Symposium, and Tillotts. J. L., B. Y. C., J. S., L. S., and F. C. are employees of Summit, Inc, and own Summit stock options. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

The human microbiome project has revolutionized our understanding of the interaction between commensal microbes and human health. By far, the biggest perturbation of the microbiome involves use of broad-spectrum antibiotics excreted in the gut. Thus, pharmacodynamics of microbiome changes in relation to drug exposure pharmacokinetics is an emerging field. However, reproducibility studies are necessary to develop the field. A simple and fast high-performance liquid chromatography-photodiode array detector (HPLC) method was validated for quantitative fecal vancomycin analysis. Reproducibility of results were tested based on sample storage time, homogeneity of antibiotic within stool, and concentration consistency after lyophilization. The HPLC method enabled the complete elution of vancomycin within ~4.2 min on the reversed-phase C18 column under the isocratic elution mode, with excellent recovery (85% to 110%) over a 4-log, quantitative range (0.4-100 μg/mL). Relative standard derivations (RSD) of intra-day and inter-day results ranged from 0.4% to 5.4%. Using sample stool aliquots of various weights consistently demonstrated similar vancomycin concentrations (mean RSD: 6%; range: 2-16%). After correcting for water concentrations, vancomycin concentrations obtained after lyophilization were similar to the concentrations obtained from the original samples (RSD less than 10%). These methodologies establish sample condition standards for a quantitative HPLC to enable vancomycin pharmacokinetic studies with the human microbiome. IMPORTANCE Research on antibiotic effect on the gut microbiome is an emerging field with standardization of research methods needed. In this study, a simple and fast high-performance liquid chromatography method was validated for quantitative fecal vancomycin analysis. Reproducibility of results were tested to standardize storage time, homogeneity of antibiotic within stool, and concentration consistency after lyophilization. These methodologies establish sample condition standards for a quantitative HPLC to enable vancomycin pharmacokinetic studies with the human microbiome.

Background: To assess the effect of fidaxomicin and vancomycin on Clostridium difficile toxins and correlation with clinical and microbiologic outcomes., Methods: Hospitalized patients with C. difficile infection were randomly assigned a 10-day course of fidaxomicin or vancomycin. Stool samples collected at baseline (day 0), mid-therapy (days 3-5), end of therapy (days 10-13) and follow-up (days 19-38) were assessed for quantity of toxins A and B as well as spore and vegetative cells counts. Correlation of toxins concentrations with microbiologic and clinical findings were evaluated., Results: Among 34 patients 12 had detectable toxin concentrations at baseline seven were randomized to fidaxomicin and five to vancomycin. Overall both fidaxomicin and vancomycin resulted in drop of both toxins concentrations by midpoint of therapy. The drop in toxin A concentrations was maintained up to the follow-up period with fidaxomicin but not with vancomycin even in patients who developed recurrence. Patients who developed recurrence in the fidaxomicin group had lower concentrations of toxin B versus the recurrence patient of vancomycin group. Presence of vegetative cells and spores was significantly linked with high toxin A (P = 0.003 and <0.001 respectively) and toxin B (P = 0.007 and <0.001 respectively) concentrations across time points. Toxin B concentrations but not A significantly correlated with stool consistency (P < 0.001) and frequency (P = 0.05)., Conclusions: Fidaxomicin was associated with sustained reduction of both toxins up to 30 days post therapy versus vancomycin. Multiple clinical or microbiologic observations were correlated with toxin A or B concentrations.

Study Objective: To assess antibiotic treatment patterns and clinical outcomes of patients with Clostridium difficile infection (CDI) based on underlying severity of CDI disease., Design: Retrospective analysis of data from a prospective cohort study., Setting: Large tertiary care university hospital., Patients: One hundred forty-four patients (mean ± SD age 63 ± 17 yrs) with CDI who received metronidazole (intravenous or oral) or oral vancomycin as their initial therapy option between 2006 and 2008., Measurements and Main Results: Patients were stratified by severity of illness and treatment, and outcomes assessed were clinical response, relapse of disease, all-cause inpatient mortality, and length of hospital stay. Mild-moderate CDI disease was present in 85 patients (59%) and severe disease in 59 patients (41%). Overall, oral vancomycin was given to 16 patients (11%); use of this drug did not differ according to severity of infection. Among patients with severe disease, clinical success occurred in 32 (63%) of 51 patients given metronidazole and in all 8 patients (100%) given vancomycin (p=0.04). Inpatient mortality and hospital length of stay were lower in patients with severe CDI who were given oral vancomycin, although these results were not statistically significant., Conclusion: Oral vancomycin was not commonly used for severe CDI. An improved clinical response rate was observed in patients with severe CDI given oral vancomycin; this outcome supported results from clinical trials. Antibiotic stewardship teams could play a major role in providing guidance on CDI treatment based on severity., (© 2012 Pharmacotherapy Publications, Inc.)

Study Objective: To determine if appropriate timing of vancomycin prophylaxis in patients undergoing cardiovascular surgery results in an economic benefit by assessing the differences in total duration of hospitalization and hospital costs based on infusion start time in relation to first surgical incision., Design: Prospective, observational study., Setting: Tertiary care medical center., Patients: A total of 1666 patients undergoing coronary artery bypass graft (CABG) and/or valve replacement surgery who received prophylactic vancomycin., Measurements and Main Results: Appropriateness of vancomycin prophylaxis timing, based on national guidelines defining appropriate timing as start time of infusion ranging from 16-120 minutes before surgery start time, was prospectively monitored. The timing of vancomycin administration was grouped as follows: 0-15 minutes (11 patients), 16-60 minutes (156), 61-120 minutes (772), or more than 120 minutes (727) before incision. Antibiotic timing was appropriate in 928 patients and inappropriate in 738 patients. Length of hospital stay and total hospital costs were compared based on appropriateness of therapy by using multivariate linear regression and validated with a Heckman two-stage model. Median numbers of hospitalization and intensive care unit days were significantly fewer in patients given appropriate prophylaxis at an appropriate time (9 and 2 days, respectively) compared with inappropriate time (10 and 3 days, respectively, p<0.001 for both analyses). Hospital costs were significantly lower in patients who had appropriate timing of antibiotic prophylaxis (median $25,321, interquartile range [IQR] $19,429-35,471) compared with inappropriate timing (median $29,475, IQR $21,507-46,488, p<0.001). Multivariate linear regression and a Heckman two-stage model confirmed that appropriate antibiotic prophylaxis timing was associated with decreased hospitalization duration and hospital costs., Conclusion: In patients undergoing CABG or valve replacement surgery, the administration of vancomycin 16-120 minutes before incision significantly reduced patient hospitalization duration and total hospital costs.

Background: Increased incidence of methicillin-resistant Staphylococcus species has required some hospitals to choose vancomycin for surgical prophylaxis. Guidelines for appropriate timing of vancomycin prophylaxis state that the infusion should begin within 120 min before the first surgical incision. However, no studies have investigated the proper timing of vancomycin prophylaxis in relationship to surgical site infections (SSI). The objective of the present study was to assess the effect of vancomycin prophylaxis timing in relation to the first surgical incision on the incidence of SSI., Methods: We prospectively monitored vancomycin prophylaxis timing and incidence of SSI in 2048 patients undergoing coronary bypass graft or valve replacement surgery. The timing of vancomycin was categorized into five groups based on the relation between the start of the infusion and the surgical cut time. Study hypotheses were tested using logistic analysis and further validated using a Heckman two-stage model., Results: The incidence of SSI were lowest in the 176 patients given vancomycin between 16 and 60 min before the surgical incision (3.4%) compared with 15 patients given vancomycin between 0 and 15 min [26.7%; relative risk (RR): 7.8; 95% CI: 2.5-24.7], 888 patients given vancomycin between 61 and 120 min (7.7%; RR: 2.2; 95% CI: 0.99-5.09), 700 patients given vancomycin between 121 and 180 min (6.9%; RR: 2.0; 95% CI: 0.87-4.62) or 269 patients given vancomycin >180 min (7.8%; RR: 2.3; 95% CI: 0.94-5.56) (P = 0.0119 by chi(2) analysis). Stepwise logistic regression analysis and a Heckman two-stage model confirmed that vancomycin administration between 16 and 60 min before the first surgical incision was associated with the lowest incidence of SSI., Conclusions: Vancomycin administration within 16-60 min before the first surgical incision reduced the risk of SSI in cardiac surgery patients.

Background: An increased prevalence of bacteremia caused by methicillin-resistant Staphylococcus aureus (MRSA) with a vancomycin hydrochloride MIC of 2 microg/mL was noted in a population of inpatients undergoing hemodialysis at Baptist Memorial Health Care, Memphis, Tennessee., Objectives: The aims of this study were to determine risk factors for infection with MRSA and to assess the differences in clinical and economic outcomes in patients undergoing hemodialysis with MRSA bacteremia with vancomycin MIC 2 microg/mL versus those with MRSA bacteremia with vancomycin MIC < or =0.5 microg/mL and uninfected controls., Methods: This retrospective case-control study was conducted at Baptist Memorial Health Care. The study population (inpatients undergoing hemodialysis for MRSA bacteremia with vancomycin MIC 2 microg/mL [high-MIC group], MIC < or = 0.5 microg/mL [low-MIC group], and uninfected controls) was identified. Risk factors and clinical and economic outcomes (costs of hospitalization, nursing, and pharmacy) were determined and compared using univariate and multivariate statistics., Results: Fifty patients with MRSA bacteremia undergoing hemodialysis were identified during the study period (high-MIC group, 17 [11 women, 6 men; mean (SD) age, 60 (17) years]; low-MIC group, 33 [23 women, 10 men; mean (SD) age, 62 (14) years]) and matched with 100 uninfected controls (57 men, 43 women; mean [SD] age, 63 [15] years). Risk factors for MRSA bacteremia found to be associated with high MIC included female sex, higher body mass index (1-point increments), recent surgery, and a history of cardiovascular disease (P < 0.05, P < 0.046, P = 0.04, and P = 0.028, respectively) (multivariate analysis). In the outcomes analysis, mortality was significantly higher in the high-MIC group compared with those in the low-MIC and control groups (35% vs 24% and 15%, respectively; P = 0.022). Total mean (SD) hospitalization costs were significantly higher in the high-MIC group compared with those in the low-MIC group and controls (US $47,624 [$80,534] vs $26,792 [$25,167] and $13,185 [$15,568], respectively; P < 0.001). Nursing costs were almost 6-fold higher in both infected groups compared with those in controls. Pharmacy costs in the low- and high-MIC groups were 3- to 6-fold higher, respectively, compared with those in controls., Conclusions: Surgery within the previous 6 months and intensive care unit admission were identified as significant risk factors for patients with MRSA bacteremia with a vancomycin MIC 2 microg/mL undergoing hemodialysis. These patients experienced a longer mean hospital length of stay and increased hospital costs compared with patients with MRSA bacteremia with a vancomycin MIC < or =0.5 microg/mL and uninfected controls.

Background: In 2001, vancomycin replaced cefuroxime for antibiotic prophylaxis in patients undergoing cardiac surgery at our institution due to high rates of surgical site infections caused by methicillin-resistant Staphylococcus spp. However, few data supported the use of vancomycin for surgical prophylaxis., Objective: To determine the tolerance of vancomycin for antibiotic prophylaxis and incidence of vancomycin-resistant Enterococcus (VRE) in cardiac surgery patients., Methods: In 2 separate studies, we assessed the adverse effects in patients given perioperative vancomycin (study 1) and the incidence of VRE in patients given perioperative vancomycin (study 2). Study 1 was a prospective cohort study of patients undergoing coronary artery bypass graft (CABG) or valve replacement surgery given vancomycin (1 dose preoperatively/2 doses postoperatively) for antibiotic prophylaxis between October 2003 and December 2004. Patients were assessed for tolerance to the antibiotic regimen. In study 2, cardiac surgery patients receiving perioperative vancomycin were screened for VRE before therapy and at day 7 of hospitalization. VRE was detected using standard microbiologic procedures., Results: In study 1, 1161 patients (CABG = 75%; valve = 19%; both = 6%) were evaluated. All patients but one (99.9%) were prescribed preoperative vancomycin. Therapy was changed for 34 (2.9%) patients, of which 20 changes were due to physician preference for another antibiotic. The only toxicity that required a change in the vancomycin regimen was red man's syndrome, which was experienced by 9 (0.8%) patients. Four patients did not receive a second postoperative dose due to prior renal insufficiency. Patients were most commonly switched to cefuroxime (n = 26), linezolid (n = 2), cefepime (n = 2), gatifloxacin, cefazolin, levofloxacin, or ceftriaxone (n = 1, each). In study 2, 100 patients were screened for the emergence of VRE colonization. No patient was VRE positive at baseline and 4 (4%) were positive at day 7., Conclusions: Surgical antibiotic prophylaxis with vancomycin was reasonably well tolerated in CABG and valve replacement surgery, with a 4% incidence of VRE colonization.

Background Clostridioides difficile infection (CDI) is a common healthcare-associated infection with limited treatment options. Omadacycline, an aminomethylcycline tetracycline, has potent in vitro activity against C difficile and a low propensity to cause CDI in clinical trials. We aimed to assess fecal pharmacokinetics and gut microbiome effects of oral omadacycline compared to oral vancomycin in healthy adults. Methods This was a phase 1, nonblinded, randomized clinical trial conducted in healthy volunteers aged 18–40 years. Subjects received a 10-day course of omadacycline or vancomycin. Stool samples were collected at baseline, daily during therapy, and at follow-up visits. Omadacycline and vancomycin stool concentrations were assessed, and microbiome changes were compared. Results Sixteen healthy volunteers with a mean age of 26 (standard deviation [SD], 5) years were enrolled; 62.5% were male, and participants' mean body mass index was 23.5 (SD, 4.0) kg/m2. Omadacycline was well tolerated with no safety signal differences between the 2 antibiotics. A rapid initial increase in fecal concentrations of omadacycline was observed compared to vancomycin, with maximum concentrations achieved within 48 hours. A significant difference in alpha diversity was observed following therapy in both the omadacycline and vancomycin groups (P <.05). Bacterial abundance and beta diversity analysis showed differing microbiome changes in subjects who received omadacycline versus vancomycin. Conclusions Subjects given omadacycline had high fecal concentrations with a distinct microbiome profile compared to vancomycin. Clinical Trials Registration NCT06030219. [ABSTRACT FROM AUTHOR]

Vancomycin is not appreciably passaged via the colonic membrane to the gastrointestinal (GI) tract in persons with an intact gut epithelium due to its large chemical structure. However; hospitalized patients with diarrhea often have a disrupted GI tract. The aim of this study was to determine the frequency of detectable vancomycin concentrations in the stool of patients with antibiotic-associated diarrhea receiving IV vancomycin. This was a multicenter cohort study of hospitalized patients with stool samples collected for Clostridioides difficile testing. Leftover stool samples were collected from patients who had received at least 3 days of IV vancomycin. Fecal vancomycin was quantified by high-performance liquid chromatography. The study cohort included 33 unique patients, majority female (54.5%) aged 60 years (range 23–84). Eighteen of thirty-three patients (54.5%) tested positive for C. difficile toxins. The average duration of systemic vancomycin administration prior to stool collection was 3.5 (range 2–15) days. Three of 33 (9%) stool samples had a detectable vancomycin concentration (range 1.2–13.2 mcg/mL). These concentrations may promote the development of vancomycin-resistant Enterococcus or van mutations in C. difficile, leading to vancomycin resistance. Further studies on implications are warranted. [ABSTRACT FROM AUTHOR]

Fulminant Clostridioides difficile infection (FCDI) encompasses 3 to 5% of all CDI cases with associated mortality rates between 30 and 40%. Major treatment modalities include surgery and medical management with antibiotic and nonantibiotic therapies. However, identification of patients with CDI that will progress to FCDI is difficult and makes it challenging to direct medical management and identify those who may benefit from surgery. Furthermore, since it is difficult to study such a critically ill population, data investigating treatment options are limited. Surgical management with diverting loop ileostomy (LI) instead of a total abdominal colectomy (TAC) with end ileostomy has several appealing advantages, and studies have not consistently demonstrated a clinical benefit with this less-invasive strategy, so both LI and TAC remain acceptable surgical options. Successful medical management of FCDI is complicated by pharmacokinetic changes that occur in critically ill patients, and there is an absence of high-quality studies that included patients with FCDI. Recommendations accordingly include a combination of antibiotics administered via multiple routes to ensure adequate drug concentrations in the colon: intravenous metronidazole, high-dose oral vancomycin, and rectal vancomycin. Although fidaxomicin is now recommended as first-line therapy for non-FCDI, there are limited clinical data to support its use in FCDI. Several nonantibiotic therapies, including fecal microbiota transplantation and intravenous immunoglobulin, have shown success as adjunctive therapies, but they are unlikely to be effective alone. In this review, we aim to summarize diagnosis and treatment options for FCDI. [ABSTRACT FROM AUTHOR]

While rates of Clostridioides difficile infection (CDI) are increasing among children in the United States, studies assessing CDI treatment in children are severely lacking. Thus, treatment guidelines have historically relied on evidence from limited observational data in children and randomized controlled trials (RCTs) conducted in adults to form recommendations. Currently, the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA) recommend metronidazole and/or vancomycin for pediatric CDI depending on disease severity. Recently however, the first and only RCT of CDI treatment in children demonstrated fidaxomicin to be non-inferior to vancomycin, proving its safety and efficacy in this population. Additionally, observational data published since the IDSA/SHEA guidelines were released suggest metronidazole has lower rates of clinical improvement when compared to vancomycin in hospitalized children with non-severe CDI. Given these recent publications, fidaxomicin and vancomycin, instead of metronidazole, appear to be more appropriate, evidence-based options for the treatment of CDI in children. [ABSTRACT FROM AUTHOR]

Background: Clostridioides difficile infection is the most common cause of healthcare-associated infections in the USA, with limited treatment options. Ibezapolstat is a novel DNA polymerase IIIC inhibitor with in vitro activity against C. difficile.Objectives and Methods: Randomized, double-blind, placebo-controlled study to assess the safety, tolerability and pharmacokinetics of ibezapolstat in healthy volunteers. Microbiome changes associated with ibezapolstat were compared with vancomycin over a 10 day course using shotgun metagenomics.Results: A total of 62 subjects aged 31 ± 7 years (45% female; average BMI: 25 ± 3 kg/m2) were randomized. Ibezapolstat was well tolerated with a safety signal similar to placebo. Ibezapolstat had minimal systemic absorption with the majority of plasma concentrations less than 1 µg/mL. In the multiday, ascending dose study, ibezapolstat concentrations of 2000 µg/g of stool were observed by Day 2 and for the remainder of the dosing time period. In the multiday, multiple-dose arm, baseline microbiota was comparable between subjects that received ibezapolstat compared with vancomycin. At Day 10 of dosing, differential abundance analysis and β-diversity demonstrated a distinct difference between the microbiome in subjects given vancomycin compared with either dose of ibezapolstat (P = 0.006). α-Diversity changes were characterized as an increase in the Actinobacteria phylum in subjects that received ibezapolstat and an increase in Proteobacteria in subjects given vancomycin.Conclusions: Ibezapolstat was shown to be safe and well tolerated, with minimal systemic exposure, high stool concentrations and a distinct microbiome profile compared with oral vancomycin. These results support further clinical development of ibezapolstat for patients with C. difficile infection. [ABSTRACT FROM AUTHOR]

Background In phase 3 MODIFY I/II trials, bezlotoxumab significantly reduced recurrence of Clostridioides (Clostridium) difficile infection (rCDI) over 12 weeks. Choice of CDI antibacterial treatment may affect CDI-related outcomes; therefore, this prespecified analysis assessed if the magnitude of bezlotoxumab-induced rCDI reduction was influenced by the antibiotic administered. Methods In MODIFY I/II (NCT01241552/NCT01513239), participants received a single infusion of bezlotoxumab (10 mg/kg) or placebo during anti-CDI treatment. Using pooled data from MODIFY I/II, initial clinical cure (ICC) and rCDI were assessed in metronidazole-, vancomycin-, and fidaxomicin-treated subgroups. Results Of 1554 participants in MODIFY I/II, 753 (48.5%) received metronidazole, 745 (47.9%) vancomycin, and 56 (3.6%) fidaxomicin. Fewer participants receiving metronidazole had a prior CDI episode in the previous 6 months (12.9%) or ≥1 risk factor for rCDI (66.0%) vs participants receiving vancomycin (41.2% and 83.6%, respectively) and fidaxomicin (55.4% and 89.3%, respectively). ICC rates were similar in the bezlotoxumab (metronidazole, 81.0%; vancomycin, 78.5%; fidaxomicin, 86.7%) and placebo groups (metronidazole, 81.3%; vancomycin, 79.6%; fidaxomicin, 76.9%). In placebo-treated participants, the rCDI was lower in the metronidazole subgroup vs the vancomycin and fidaxomicin subgroups (metronidazole, 28.0%; vancomycin, 38.4%; fidaxomicin, 35.0%). When analyzed by subsets based on history of CDI, rCDI rates were similar in the metronidazole and vancomycin groups. rCDI rates were lower in all antibiotic subgroups for bezlotoxumab vs placebo (metronidazole: rate difference [RD], –9.7%; 95% confidence interval [CI], –16.4% to –3.1%; vancomycin: RD, –15.4%; 95% CI, –22.7% to –8.0%; fidaxomicin: RD, –11.9%; 95% CI, –38.1% to 14.3%). Conclusion Bezlotoxumab reduces rCDI vs placebo in participants receiving metronidazole and vancomycin, with a similar effect size in participants receiving fidaxomicin. [ABSTRACT FROM AUTHOR]

Objectives: To describe, for the first time (to the best of our knowledge), the genetic mechanisms of vancomycin resistance in clinical isolates of Clostridioides difficile ribotype 027.Methods: Clinical isolates and laboratory mutants were analysed: genomically to identify resistance mutations; by transcriptional analysis of vanGCd, the vancomycin resistance operon encoding lipid II d-alanine-d-serine that is less bound by vancomycin than native lipid II d-alanine-d-alanine; by imaging of vancomycin binding to cell walls; and for changes in vancomycin bactericidal activity and autolysis.Results: Vancomycin-resistant laboratory mutants and clinical isolates acquired mutations to the vanSR two-component system that regulates vanGCd. The substitutions impaired VanSR's function, resulting in constitutive transcription of vanGCd. Resistance was reversed by silencing vanG, encoding d-alanine-d-serine ligase in the vanGCd operon. In resistant cells, vancomycin was less bound to the cell wall septum, the site where vancomycin interacts with lipid II. Vancomycin's bactericidal activity was reduced against clinical isolates and laboratory mutants (64 and ≥1024 mg/L, respectively) compared with WT strains (4 mg/L). Truncation of the potassium transporter TrkA occurred in laboratory mutants, which were refractory to autolysis, accounting for their survival in high drug concentrations.Conclusions: Ribotype 027 evolved first-step resistance to vancomycin by constitutively expressing vanGCd, which is otherwise silent. Experimental evolutions and bactericidal assays show that ribotype 027 can acquire mutations to drastically enhance its tolerance to vancomycin. Thus, further epidemiological studies are warranted to examine the extent to which vancomycin resistance impacts clinical outcomes and the potential for these strains to evolve higher-level resistance, which would be devastating. [ABSTRACT FROM AUTHOR]

Blood culture contamination with gram-positive organisms is a common occurrence in patients suspected of bloodstream infections, especially in emergency departments. Although numerous research studies have investigated the cost implications of blood culture contamination, a contemporary systematic review of the literature has not been performed. The aim of this project was to perform a systematic review of the published literature on the economic costs of blood culture contamination. PubMed was searched (January 1, 1978, to July 15, 2018) using the search terms "blood culture contamination" or "false-positive blood cultures." Articles were title searched and abstracts were reviewed for eligible articles that reported immediate or downstream economic costs of blood culture contamination. The PubMed search identified 151 relevant articles by title search, with 49 articles included after abstract review. From the studies included, overall blood culture contamination rates ranged from 0.9%-41%. Up to 59% of patients received unnecessary treatment with parenteral vancomycin as a result of blood culture contamination, resulting in increased pharmacy charges between $210 and $12,611 per patient. Increases in total laboratory charges between $2,397 and $11,152 per patient were reported. Attributable hospital length of stay increases due to blood culture contamination ranged from 1-22 days. This systematic review of the literature identified several areas of health care expenditure associated with blood culture contamination. Interventions to reduce the risk of blood culture contamination would avoid downstream economic costs. [ABSTRACT FROM AUTHOR]

Background ACX-362E, a novel DNA polIIIC inhibitor, is a narrow-spectrum antibacterial selectively active against certain Gram-positive bacteria, including Clostridioides difficile (MIC90 = 4 µg/mL). The objectives of this phase I study was to assess the safety, pharmacokinetics, and fecal microbiome effects of ACX-362E Methods This three-part FIH phase 1, double-blind, randomized healthy volunteer trial determined the safety profile, food effect, and systemic/stool pharmacokinetics of escalating single (150, 300, 600, and 900 mg) and multiple (300 and 450 mg) doses of oral ACX-362E vs. placebo (PBO). Fecal microbiome effects (metagenomic sequencing and qPCR) of multiple-dose ACX-362E were compared with 6 subjects receiving concomitant open-label vancomycin 125 mg four times daily. Dose escalation to each new cohort occurred following review of safety and PK data by a safety oversight committee. Results Forty-four subjects received ACX-362E (single dose = 24, multiple doses = 12, food effect = 8) and 12 PBO. Overall, ACX-362E was well tolerated at all dose levels. Adverse events were generally mild and transitory, and no moderate, severe, cumulative, or dose-limiting drug-related adverse events leading to discontinuation were observed. Mean plasma half-life was approximately 2 hours and no accumulation occurred with repeated dosing (Figure 1). Systemic exposure was less than 1 μg/mL and decreased with food. Fecal concentrations during multiple dosing exceeded the C. difficile MIC by multiples of up to ~2,500. ACX-362E had minimal effect on Bacteroidetes phylum and caused significantly less dysbiosis than vancomycin (Figure 2). Conclusion This FIH clinical trial with ACX-362E demonstrated a favorable safety profile, low systemic and high fecal concentrations, and favorable gut microbiome changes compared with vancomycin. These results shows promise for further clinical development to treat C. difficile infections. Disclosures Kevin W. Garey, MS, PharmD, Acurx (Grant/Research Support), Martin Kankam, MD, PhD, MPH, Acurx Pharmaceuticals, LLC (Research Grant or Support), Julie Mercier, BS, Acurx Pharmaceuticals, LLC (Research Grant or Support), Corinne Seng Yue, BPharm, MSc, PhD, Acurx Pharmaceuticals, LLC (Grant/Research Support), Murray Ducharme, PharmD, Acurx Pharmaceuticals, LLC (Grant/Research Support), Anne J. Gonzales-Luna, PharmD, no financial relationships or conflicts of interest, M Jahangir Alam, PhD, No financial relationships or conflicts of interest, Khurshida Begum, PhD, No financial relationships or conflicts of interest, Michael Silverman, MD, Acurx Pharmaceuticals, LLC (Consultant, Employee, Shareholder). [ABSTRACT FROM AUTHOR]

Background Eravacycline is a novel, tetracycline class antibacterial indicated for the treatment of complicated intra-abdominal infections in adults. In clinical trials, patients given eravacycline had a low likelihood of developing Clostridioides difficile infection (CDI). We hypothesized this was likely due, in part, to the in vitro susceptibility of eravacycline to C. difficile. The purpose of this study was to test the in vitro susceptibility of eravacycline vs. comparators on contemporary clinical isolates representing common ribotypes, including isolates with decreased susceptibility to metronidazole and vancomycin. Methods Two hundred and thirty-four isolates from our biobank were selected from the six most common ribotypes (F001, F002, F014-020, F027, F106, and F255). Minimum inhibitory concentrations (MIC) at 24 hours were measured according to CLSI guidelines for eravacycline, vancomycin, metronidazole and fidaxomicin. MICs results were tabulated and are presented as the geometric mean by ribotype. Results Geometric MIC results are shown in Table 1. Eravacycline was the most potent antimicrobial tested followed by fidaxomicin, metronidazole, and vancomycin. Results were consistent amongst all ribotypes, including isolates with reduced susceptibility to vancomycin and metronidazole. Conclusion Eravacycline displayed potent in vitro activity against a large collection of clinical C. difficile isolates. These data provide insight into why patients given eravacycline had a low likelihood of developing CDI and support further research to better understand the use of eravacycline to prevent or potentially treat patients with CDI. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]

Background Antimicrobials disrupt the gut microbiota by reducing gut microbiome diversity and quantity. Galleria mellonella provides an invertebrate model that is inexpensive, easy to maintain, and does not require specialized equipment. This study investigated the feasibility of using G. mellonella as an in vivo model to evaluate the effect of different antimicrobials on gut microbiota. Methods To determine baseline gut microbiota composition, the gut contents of G. mellonella were extracted and genomic DNA underwent shotgun meta-genomic sequencing. To determine the effect of infection and antibiotic use, 30 larvae were injected (left proleg) with ~1 × 105 colony-forming unit (cfu) of methicillin-resistant Staphylococcus aureus (MRSA) and were randomized 1:1:1 to treatment with vancomycin (20 mg/kg) or a natural antimicrobial (Nigella sativa seed oil, 70 mg/kg; NS oil), or a combination. The larvae were kept at 37°C post-infection and monitored daily for 72 hours for activity, extent of cocoon formation/growth, melanization, and survival. Two larvae from each group were randomly selected and homogenized with PBS as controls. After 24 hours of incubation, gut contents were extracted and plated for MRSA and Enterococcus cfu counts. Results Metagenomics analysis showed the gut microbiota composition of G. mellonella larvae was dominated by a subset of closely-related Enterococcus species. After 24 hours of exposure, mean Enterococcus counts were 4 × 103 cfu in the vancomycin arm and 6.2 × 104 cfu in the NS oil arm. Mean MRSA counts were 3.3 × 105 cfu in vancomycin arm and 1.5 × 104 cfu in NS oil arm. The combination of vancomycin and NS oil had higher Enterococcus counts than the vancomycin alone arm (6.3 × 104 cfu vs. 4 × 103 cfu, respectively), suggesting that NS oil may have a role in protecting the gut microbiota. Conclusion This study provides preliminary evidence to support the potential use of G. mellonella to assess the in vivo effect of a natural and synthetic antimicrobial on the gut microbiota. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]

Background Methods to operationalize antibiotic timeouts (ATO) among hospitalized patients are often constrained by the high volume of antibiotic orders that surpass the capabilities of the antimicrobial stewardship program (ASP) to intervene. Houston Methodist Hospital implemented a streamlined electronic ATO process that alerted providers to evaluate the need for continued antibiotics on day 4 of predefined anti-infective therapy. Unresolved alerts were reviewed by clinical pharmacists the following day. The objective of this study was to determine the impact of this electronic ATO on frequently prescribed antibiotics. Methods This was a quasi-experimental study in a 924-bed quaternary care hospital comparing days of therapy (DOT) in patients admitted prior to (February 2017 – January 2018) and after implementing an ATO process (March 2018 – February 2019). Antibiotics evaluated included vancomycin, cefepime, piperacillin/tazobactam, and meropenem. ATO alert logic was simulated retrospectively to capture the pre-ATO cohort. The primary outcome was mean composite DOT per patient admission. Secondary outcomes included total hospitalization cost, Clostridioides difficile infection (CDI) and multidrug-resistant organism (MDRO) rates. Results A total of 8,458 patients met ATO alert criteria for inclusion in the pre-ATO timeframe and 6,901 patients with an ATO alert in the post-ATO group; 2,642 (38%) prompted a pharmacists' review. The average composite DOT was 11.5 per admission in the pre-ATO cohort compared with 11.1 in the post-ATO cohort (P = 0.02). After multivariate linear regression, the ATO was significantly associated with a decrease of 0.5 DOT per patient admission (P < 0.001). Other factors associated with a reduction in DOT included age (P < 0.001), service line (P = 0.003), and admission source (P = 0.031). Mean hospital costs per admission were significantly reduced in the post-ATO group: $67,613 vs. $66,615 (P = 0.01). There was no difference in rates of CDI and MDRO. Conclusion Implementation of our electronic ATO process demonstrated significant reductions in overall DOT for frequently prescribed antibiotics and decreased total hospital costs across a diverse patient population. This process provides a real-world strategy to operationalize a large-scale ATO as an adjunct to an ASP. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]

Background C. difficile is the most frequent hospital-acquired bacteria in the United States. CDI is associated with significant morbidity and mortality, and a 46% lower mean EQ-5D index of Health-Related Quality of Life (HRQoL) compared with the general population. However, data on the impact of antibiotic treatment for CDI on HRQoL are lacking. Methods RDZ is a novel, narrow-spectrum antibiotic with targeted activity against C. difficile , under development for the treatment of CDI and prevention of recurrence. We evaluated HRQoL prospectively with the EQ-5D-3L in 69 patients enrolled in a Phase 2 randomized, double-blind trial comparing RDZ (n = 36) with VAN (n = 33). EQ-5D-3L was obtained at five time points (baseline, days 5, 10, 12, and 40) with summary index values calculated using US weights (Shaw 2005) evaluating raw scores for mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, and visual analog scale (VAS) scores. Results As early as Day 5, CDI patients on RDZ had significant improvements in mean change from baseline in index scores (P = 0.008) and VAS scores (P = 0.01) but no significant improvements were seen in patients on VAN. Time to resolution of diarrhea also occurred sooner with RDZ with a hazard ratio 1.19 in favor of RDZ (90% CI: 0.76, 1.87). Mean changes in index scores in the VAN group took longer to improve significantly compared with baseline and became higher on VAN on Day 12 and Day 40. Treatment-related improvements in pain/discomfort and anxiety/depression are shown in Figures 1 and 2. The mean change from baseline in EQ-5D-3L domains showed the highest (significant) improvements in the pain/discomfort domain for both treatment groups across all time points. However, by Day 40, anxiety/depression improved significantly more with RDZ than with VAN (P = 0.039). Conclusion We believe this is the first study to document improvements in HRQoL after antimicrobial treatment for CDI. Patients receiving ridinilazole experienced greater improvements in HRQoL sooner than those on VAN. Anxiety/depression and pain/discomfort improved significantly with treatment. HRQoL should be evaluated in Phase 3 interventional studies for CDI. These results will need to be validated in the ongoing Phase 3 randomized, double-blind, global trials comparing RDZ to VAN for the treatment of CDI. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]

Background Fecal microbiota transplantation (FMT) is recommended to treat refractory or recurrent cases of Clostridioides difficile infection (CDI) through restoration of a healthy intestinal microbiome. The procedure has reported success rates of 90% or higher for CDI, but several risk factors for FMT failure have been identified. Here we present a case of a patient failing four FMT procedures over a 2-year period, with accompanying microbiome and metagenomic analyses. Methods Seven serial C. difficile -positive stool samples were collected as part of an ongoing surveillance system in Texas. Samples, including the index case, represented independent CDI episodes interspersed between four separate FMT procedures between 2016 and 2018. PCR ribotype (RT) testing, 16S rRNA gene sequencing, MIC testing, multidrug-resistant organism (MDRO) screening, and shotgun metagenome sequencing were conducted for each of the samples. Results The patient was a 42-year-old female with various comorbidities, including systemic lupus erythematosus. She received continuous non-CDI antibiotic courses throughout her CDI therapy for a variety of infections. The vancomycin MICs in infecting C. difficile strains increased with cumulative vancomycin exposure. Multidrug-resistant organisms were detected in stool, including Enterococcus spp. MRSA, and Candida glabrata. The first five of the seven strains were RT 078–126, one was mixed RT 002 and RT 054, and one was RT 002. The analysis of 16S rRNA gene sequences demonstrated that microbial diversity was never restored after FMT procedures. A strong correlation between microbial and functional gene compositions suggests that fecal samples share many microbial species with associated functional genes. Conclusion A number of systems biology changes were observed in a patient with persistent CDI despite multiple FMTs. The lack of FMT engraftment was most likely due to continuous broad-spectrum antibiotic exposure in an immunocompromised patient. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]

Clostridium difficile is a significant cause of nosocomial-acquired infection that results in severe diarrhea and can lead to mortality. Treatment options for C . difficile infection (CDI) are limited, however, new antibiotics are being developed. Current methods for determining efficacy of experimental antibiotics on C . difficile involve antibiotic killing rates and do not give insight into the drug's pharmacologic effects. Considering this, we hypothesized that by using scanning electron microscopy (SEM) in tandem to drug killing curves, we would be able to determine efficacy and visualize the phenotypic response to drug treatment. To test this hypothesis, supraMIC kill curves were conducted using vancomycin, metronidazole, fidaxomicin, and ridinilazole. Following collection, cells were either plated or imaged using a scanning electron microscope (SEM). Consistent with previous reports, we found that the tested antibiotics had significant bactericidal activity at supraMIC concentrations. By SEM imaging and using a semi-automatic pipeline for image analysis, we were able to determine that vancomycin and to a lesser extent fidaxomicin and ridinilazole significantly affected the cell wall, whereas metronidazole, fidaxomicin, and ridinilazole had significant effects on cell length suggesting a metabolic effect. While the phenotypic response to drug treatment has not been documented previously in this manner, the results observed are consistent with the drug's mechanism of action. These techniques demonstrate the versatility and reliability of imaging and measurements that could be applied to other experimental compounds. We believe the strategies laid out here are vital for characterizing new antibiotics in development for treating CDI. [ABSTRACT FROM AUTHOR]

Clostridium difficile infection (CDI) is the leading cause of infectious healthcare-associated diarrhoea. Recurrent CDI increases disease morbidity and mortality, posing a high burden to patients and a growing economic burden to the healthcare system. Thus, there exists a significant unmet and increasing medical need for new therapies for CDI. This review aims to provide a concise summary of CDI in general and a specific update on ridinilazole (formerly SMT19969), a novel antibacterial currently under development for the treatment of CDI. Owing to its highly targeted spectrum of activity and ability to spare the normal gut microbiota, ridinilazole provides significant advantages over metronidazole and vancomycin, the mainstay antibiotics for CDI. Ridinilazole is bactericidal against C. difficile and exhibits a prolonged post-antibiotic effect. Furthermore, treatment with ridinilazole results in decreased toxin production. A phase 1 trial demonstrated that oral ridinilazole is well tolerated and specifically targets clostridia whilst sparing other faecal bacteria. Phase 2 and 3 trials will hopefully further our understanding of the clinical utility of ridinilazole for the treatment of CDI. [ABSTRACT FROM AUTHOR]