Oral Vancomycin Treatment Research Articles

Open label vancomycin in primary sclerosing cholangitis-inflammatory bowel disease: improved colonic disease activity and associations with changes in host-microbiome-metabolomic signatures.

We conducted a single-arm interventional study, to explore mucosal changes associated with clinical remission under oral vancomycin (OV) treatment, in primary sclerosing cholangitis associated inflammatory bowel disease (PSC-IBD); NCT05376228. Fifteen patients with PSC and active colitis (median faecal calprotectin 459µg/g; median total Mayo score 5) were treated with OV (125mg QID) for 4 weeks and followed-up for a further 4 weeks of treatment withdrawal (8 weeks, end-of-study). Colonic biopsies were obtained at baseline and week 4. Clinical assessments, and serum and stool samples (metagenomics, metatranscriptomics and metabolomics) were collected at weeks 0, 2, 4 and 8. The primary efficacy outcome measure was induction of clinical remission. OV resulted in clinical remission in 12/15 patients and significant reductions in faecal calprotectin. OV was associated with reduced abundances of Lachnospiraceae, genera Blautia and Bacteroides; and enrichment of Enterobacteriaceae, and genera Veillonella, Akkermansia and Escherichia. OV treatment was associated with downregulation of multiple metatranscriptomic pathways (including short chain fatty acid [SCFA] metabolism and bile acid [BA] biotransformation), along with host genes and multiple pathways involved in inflammatory responses and antimicrobial defence; and an upregulation of genes associated with extracellular matrix repair. OV use resulted in loss of specific faecal SCFAs and secondary BAs, including lithocholic acid derivatives. Colitis activity relapsed following OV withdrawal, with host mucosal and microbial changes trending towards baseline. Four weeks of OV induces remission in PSC-IBD activity, associated with a reduction in gut bacterial diversity and compositional changes relating to BA and SCFA homeostasis.

Impact of oral vancomycin treatment duration on rate of Clostridioides difficile recurrence in patients requiring concurrent systemic antibiotics.

There is a paucity of data guiding treatment duration of oral vancomycin for Clostridiodes difficile infection (CDI) in patients requiring concomitant systemic antibiotics. To evaluate prescribing practices of vancomycin for CDI in patients that required concurrent systemic antibiotics and to determine whether a prolonged duration of vancomycin (>14 days), compared to a standard duration (10-14 days), decreased CDI recurrence. In this retrospective cohort study, we evaluated adult hospitalized patients with an initial episode of CDI who were treated with vancomycin and who received overlapping systemic antibiotics for >72 hours. Outcomes of interest included CDI recurrence and isolation of vancomycin-resistant Enterococcus (VRE). Among the 218 patients included, 36% received a standard duration and 64% received a prolonged duration of treatment for a median of 13 days (11-14) and 20 days (16-26), respectively. Patients who received a prolonged duration had a longer median duration of systemic antibiotic overlap with vancomycin (11 vs 8 days; P < .001) and significantly more carbapenem use and infectious disease consultation. Recurrence at 8 weeks (12% standard duration vs 8% prolonged duration; P = .367), recurrence at 6 months (15% standard duration vs 10% prolonged duration; P = .240), and VRE isolation (3% standard duration vs 9% prolonged duration; P = .083) were not significantly different between groups. Discontinuation of vancomycin prior to completion of antibiotics was an independent predictor of 8-week recurrence on multivariable logistic regression (OR, 4.8; 95% CI, 1.3-18.1). Oral vancomycin prescribing relative to the systemic antibiotic end date may affect CDI recurrence to a greater extent than total vancomycin duration alone. Further studies are needed to confirm these findings.

Oral vancomycin treatment suppresses gut trypsin activity and preserves intestinal barrier function during EAE

Studies have reported increased intestinal permeability in multiple sclerosis (MS) patients and its mouse model experimental autoimmune encephalomyelitis (EAE). However, the mechanisms driving increased intestinal permeability that in turn exacerbate neuroinflammation during EAE remain unclear. Here we showed that vancomycin preserved the integrity of the intestinal barrier, while also suppressing gut trypsin activity, enhancing the relative abundance of specific Lactobacilli and ameliorating disease during EAE. Furthermore, Lactobacilli enriched in the gut of vancomycin-treated EAE mice at day 3 post immunization negatively correlated with gut trypsin activity and EAE severity. In untreated EAE mice, we observed increased intestinal permeability and increased intestinal protease activated receptor 2 (PAR2) expression at day 3 post immunization. Prior studies have shown that trypsin increases intestinal permeability by activating PAR2. Our results suggest that the interaction between intestinal PAR2 and trypsin may be a key modulator of intestinal permeability and disease severity during EAE.

Coexisting cytomegalovirus colitis in an immunocompetent patient with Clostridioides difficile colitis: A case report

Clostridioides difficile (C. difficile) colitis is one of the most common infections in hospitalized patients, characterized by fever and diarrhea. It usually improves after appropriate antibiotic treatment; if not, comorbidities should be considered. Cytomegalovirus (CMV) colitis is a possible co-existing diagnosis in patients with C. difficile infection with poor treatment response. However, compared with immunocompromised patients, CMV colitis in immunocompetent patients is not well studied. We present an unusual case of co-existing CMV colitis in an immunocompetent patient with C. difficile infection. An 80-year-old female patient was referred to the infectious disease department due to diarrhea, abdominal discomfort, and fever for 1 wk during her hospitalization for surgery. C. difficile toxin B polymerase chain reaction on stool samples was positive. After C. difficile infection was diagnosed, oral vancomycin treatment was administered. Her symptoms including diarrhea, fever and abdominal discomfort improved for ten days. Unfortunately, the symptoms worsened again with bloody diarrhea and fever. Therefore, a sigmoidoscopy was performed for evaluation, showing a longitudinal ulcer on the sigmoid colon. Endoscopic biopsy confirmed CMV colitis, and the clinical symptoms improved after using ganciclovir. Co-existing CMV colitis should be considered in patients with aggravated C. difficile infection on appropriate treatment, even in immunocompetent hosts.

391. Evaluation of oral vancomycin treatment for hospital-acquired Clostridioides difficile infection prophylaxis in a community hospital: A retrospective cohort study

Abstract Background Hospital-acquired (HA) Clostridioides difficile infection (CDI) is among the most common hospital-acquired infections and is a leading cause of morbidity and mortality among hospitalized older adults. Oral vancomycin prophylaxis (OVP) has been demonstrated in recent studies to reduce the incidence of HA CDI. This study aims to evaluate the effectiveness of OVP in the prevention of HA CDI in a community hospital setting. Methods We developed a protocol to administer prophylactic oral vancomycin based on patients’ risk factors and implemented it at our community hospital in Evanston, Illinois, in September 2020. The intervention group consists of patients admitted to our hospital between October 1, 2020, to March 31, 2021, who received OVP. Patients admitted between October 1, 2019, to March 31, 2020, who had at least one risk factor of CDI and met the inclusion criteria of OVP protocol were selected as the control group. Electronic medical records were retrospectively collected and analyzed. Propensity score matching was performed for a one-to-one match between two groups. Logistic regression models were used to study the relationship between HA CDI and independent variables, including OVP, risk factors of CDI, and demographic characteristics. Table 1.Sample characteristics of the control and intervention groups A Student t-test was performed for continuous parameters. A Chi-square test was performed for categorical parameters. Non PPx = control group; OVP PPx = oral vancomycin prophylaxis group; SNF = skilled nursing facility; LOS = length of stay; PPI = proton pump inhibitor; H2RA = histamine 2 receptor antagonist. Results A total of 446 patients (267 in the intervention group and 179 in the control group) were included. The sample characteristics are summarized in Table 1. 4/175 (2.2%) patients in the control group developed HA CDI, compared with 12/255 (4.5%) in the intervention group. Before matching, patients who received OVP (OR=7.62, p=0.010) and had a longer length of stay (LOS, OR=1.11, p=0.002) were found to have increased odds ratios (OR) of development of HA CDI (Table 2). After propensity score matching, 4/176 (2.3%) patients in the control group developed HA CDI, compared with 5/176 (2.8%) (Figure 1). Patients from skilled nursing facilities (SNF, OR=15.41, p=0.021) and with longer LOS (OR 1.15, p=0.005) were found to be associated with higher OR of HA CDI (Table 3). Table 2.The odds ratio of development of hospital-acquired C.diff infection among control and intervention groups. A binary logistic regression model was used for this study. CI = 95% confidence interval. R2 Tujur = coefficients of determination (D); AIC = Akaike’s Information Criteria. OVP PPx = oral vancomycin prophylaxis group; SNF = skilled nursing facility; LOS = length of stay; PPI = proton pump inhibitor; H2RA = histamine 2 receptor antagonist. Figure 1.Propensity score matching of control and intervention groups. (A) Distribution of propensity scores between unmatched and matched control and intervention groups. (B) Distribution balance of propensity score before and after matching. Treatment o = control group; Treatment 1 = OVP intervention group. (C) The distribution balance of covariates used for propensity score calculation before and after matching. (D) Summary of propensity score matching results. HA CDI = hospital-acquired C.diff infection (after propensity score matching). Table 3.The odds ratio of development of hospital-acquired C.diff infection among control and intervention groups after propensity score matching. A binary logistic regression model was used for this study. CI = 95% confidence interval. R2 Tujur = coefficients of determination (D); AIC = Akaike’s Information Criteria. OVP PPx = oral vancomycin prophylaxis group; SNF = skilled nursing facility; LOS = length of stay; PPI = proton pump inhibitor; H2RA = histamine 2 receptor antagonist. Conclusion Prophylactic administration of oral vancomycin to patients with selected risk factors has no statistical significance in reducing or preventing HA CDI. A longer length of hospital stay may be associated with higher risk for developing HA CDI. Disclosures All Authors: No reported disclosures.

Use of oral vancomycin in children with autoimmune liver disease: A single centre experience.

BACKGROUNDPrevious reports showed some beneficial effect of oral vancomycin treatment (OVT) in children with primary sclerosing cholangitis; conversely, the experience in patients with other autoimmune liver diseases (AILD), including autoimmune hepatitis (AIH) and autoimmune sclerosing cholangitis (ASC), is scant. AIMTo assess the response to immunosuppressive treatment (IS) and to OVT in children diagnosed with AILD.METHODSRetrospective study of children diagnosed with AIH (normal biliary tree at cholangiography) and ASC (abnormal biliary tree at cholangiography) in the last 10 years. All underwent standard immunosuppressive therapy (IS), but non-responders received also OVT. Biochemical remission [normal aspartate aminotransferase (AST)] and immunological remission (normal IgG and negative autoantibodies) rates and Sclerosing Cholangitis Outcomes in Pediatrics (SCOPE) index were assessed and compared during the follow up.RESULTS75 children were included [69% female, median age 10.5 years (5.6-13.4 years), AIH = 54, ASC= 21]. Sixty-three patients (84%, AIH = 52, ASC = 11) were treated with standard IS and 61 achieved biochemical remission, whereas 12 not responding to IS [16%, F = 75%, median age 13.5 years, (12.2-15.7), 10 with ASC] required OVT and 8 achieved biochemical remission. Overall OVT increased the biochemical remission rate of the whole group of AILD patients from 81% (61/75) to 92% (69/75). Median values of AST, alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) decreased significantly after OVT start (P < 0.05). Complete normalization of livers enzymes (AST, ALT and GGT) was observed in 6/12 patients (50%). Decrease in SCOPE index score was reported in 5/12 patients (42%). At last follow up (median of 4.4 years, range 0.6-13.8 years) all 75 patients are alive, 6 (8%, 1 with ASC) successfully discontinued medications, 1 (with ASC) required liver transplantation.CONCLUSIONChildren with AIH and ASC respond well to IS treatment. OVT may represent a valuable treatment option to achieve biochemical remission in patients not responding to standard IS. These promising preliminary results suggest that a prospective study is indicated to define the efficacy of OVT in AILD.

762. Real-World Utilization of C. difficile Drug Treatments and Associated Clinical Outcomes in a US Hospital System

BackgroundIDSA recommends use of fidaxomicin or oral vancomycin for treatment of initial episode or first recurrence of Clostridioides difficile infection (CDI). This study aimed to evaluate impact of a clinical decision support order set driving appropriate use of fidaxomicin on utilization of CDI drug treatments and associated clinical outcomes. MethodsThis was a retrospective, quasi-experimental study evaluating CDI therapies pre- (8/2016-11/2017) and post- (5/2018-1/2020) CDI order set implementation at a level-one trauma center located in Virginia. Admitted adult patients were included if CDI testing was positive for a 1st or 2nd episode and received active CDI treatment. Exclusions included fulminant CDI and CDI diagnosis by PCR with < 3 bowel movements or laxative use within 24 hours. The primary outcome was CDI recurrence within 30 days of completing therapy in patients who achieved clinical cure. Secondary outcomes were evaluated at 30 and 90 days and included sustained response and CDI-related readmissions. ResultsAfter screening, 186 patients in the pre-group and 187 in the post-group were included. Median age was 68 [59-77], most patients had an initial CDI episode (88.2%) and were diagnosed with severe CDI (50.7%). Baseline characteristics were similar between each group on Charlson comorbidity index, ICU admission, CDI risk factors, and concomitant antibiotic use. Primary treatment options in the pre-group were most commonly metronidazole 47.9% and oral vancomycin 50.5%, and in the post-group were fidaxomicin 56.7% and oral vancomycin 41.7% (Figure 1). CDI recurrence rates at 30 days post-index medication (17.2% vs. 6.3%, p=0.004) were lower in the post-group (Table 1). Clinical cure (84.4% vs. 94.1%, p=0.002) and sustained response at 90 days (55.9% vs. 73.3%, p< 0.001) were higher in the post-group. CDI recurrence rates at 90 days and CDI-related readmissions at 30 and 90 days were also lower in the post group.Figure 1. CDI Treatment Utilization Table 1. Clinical Outcomes ConclusionImplementation of the CDI order set increased fidaxomicin use and was associated with a decrease in CDI recurrences and CDI-related readmissions and increase in clinical cure and sustained response. Findings suggest increased first-line use of fidaxomicin results in better clinical outcomes.Disclosures Lauren McDaniel, Pharm.D., BCIDP, Merck Sharp & Dohme Corp (Grant/Research Support) Nathan Everson, Pharm.D., BCIDP, AAHIVE, Merck & Co. (Grant/Research Support) Melissa White, PharmD, Merck Sharpe & Co (Grant/Research Support) Engels N. Obi, PhD, Merck & Co. (Employee, Shareholder) Yiyun Chen, PhD, Merck & Co., Inc (Employee) Rose Kohinke, PharmD, Merck Sharpe & Co (Research Grant or Support)

763. Impact of Two-Step Testing Algorithm on Hospital-onset Clostridioides difficile Infections and Oral Vancomycin Prescription Practices at an Academic Medical Center

Background Clostridioides difficile infection (CDI) is one of the leading causes of hospital –onset (HO) infections. Clinically distinguishing true CDI versus colonization with C.difficile is challenging. We implemented a two-step testing algorithm to discriminate true CDI from colonization then evaluated the effect on rate of HO CDI and oral vancomycin. MethodsIn May 2020, a two-step testing algorithm was implemented utilizing C. difficile PCR and enzyme immunoassay (EIA) glutamate dehydrogenase (Figure 1). Rates of HO CDI and use of oral vancomycin was compared in the three quarters preceding and after this intervention (July 2019-March 2020 and July 2020-March 2021, respectively). HO CDI was defined based on National Healthcare Safety Network (NHSN) Laboratory Identified (LabID) event as last positive C.difficile test result performed on a specimen collected >3 calendar days after admission to the facility. HO CDI rates were assessed based on Standardized Infection Ratio (SIR) data and antimicrobial use was reported in days of therapy (DoT) per 1000 patient days. Figure 1. Two-Step Testing Algorithm for Diagnosing Clostridioides difficile infection ResultsDuring the pre-intervention period 30 HO CDI cases were reported compared to 9 cases in the post-intervention period (p=0.02) (Figure 2). There was a non-statistically significant reduction in CDI SIR in post-intervention period (0.133 vs. 0.305, p=0.11). Oral vancomycin use was similar in the pre- and post-intervention periods (3.89 vs. 3.84, p=0.96). Fidaxomicin use was rare (< 0.2 DoT/1000 pt days). Of 26 HO C.difficile colonized patients in post-intervention period, 14 (54%) patients received oral vancomycin treatment. Infectious diseases was consulted on 7/14 and recommended discontinuation of treatment in 3 while treatment was continued for other patients based on clinical status and immunocompromising conditions. Figure 2. Comparison of pre- and post-intervention trend in Hospital-onset CDI rate ConclusionWe successfully reduced our HO CDI infections and SIR below national average after implementation of two-step testing algorithm for CDI. There was no impact on the rate of oral vancomycin use. We observed at 54% rate of treatment for patients categorized as likely colonization. Provider education and stewardship interventions are necessary to reduce inappropriate use of oral vancomycin in colonized patients. Disclosures All Authors: No reported disclosures

Impact of Clostridioides difficile Therapy on Nosocomial Acquisition of Vancomycin-Resistant Enterococci.

Vancomycin is frequently used for the treatment of C. difficile infections (CDI). There are concerns that this might increase the risk of selecting vancomycin resistant enterococci (VRE). Here, we evaluated whether there is an increased risk of VRE acquisition following vancomycin for CDI specific treatment. Patients with CDI, metronidazole, or oral vancomycin treatment and without preexisting VRE were monitored for VRE acquisition. VRE isolates from patients with acquired and preexisting colonization were collected and subjected to whole genome sequencing. In total, 281 patients (median age 56 years, 54% of the male sex) presented with toxin positive C. difficile. Of them, 170 patients met the inclusion criteria, comprising 37 patients treated with metronidazole and 133 treated with oral vancomycin. In total, 14 patients meeting the inclusion criteria acquired VRE (vancomycin: n = 11; metronidazole: n = 3). Statistical analysis revealed no significant differences between both VRE acquisition rates. Genetic comparison of detected VRE isolates resulted in eight clusters of closely related genotypes comprising acquired and preexisting strains. Our results suggest that vancomycin and metronidazole likewise increase the risk of VRE acquisition. Genetic comparison indicates that VRE acquisition is a result of both antibiotic selection and pathogen transmission.

Roles of Phytoestrogen in the Pathophysiology of Intracranial Aneurysm

The incidences of intracranial aneurysm and aneurysmal subarachnoid hemorrhage are high in postmenopausal women. Although population-based studies suggest that hormone replacement therapy is beneficial for postmenopausal women with intracranial aneurysms, estrogen replacement may no longer be recommended for the prevention of chronic diseases given its association with adverse outcomes, such as cancer and ischemic stroke. The isoflavone daidzein and its intestinal metabolite equol are bioactive phytoestrogens and potent agonists of estrogen receptors. Given their estrogenic properties, we investigated whether the isoflavones daidzein and equol are protective against the formation and rupture of intracranial aneurysms in a mouse model of the postmenopausal state. We induced intracranial aneurysms in ovariectomized adult female mice using a combination of induced systemic hypertension and a single injection of elastase into the cerebrospinal fluid. We fed the mice with an isoflavone-free diet with/without daidzein supplementation, or in a combination of intraperitoneal equol, or oral vancomycin treatment. We also used estrogen receptor beta knockout mice. Both dietary daidzein and supplementation with its metabolite, equol, were protective against aneurysm formation in ovariectomized mice. The protective effects of daidzein and equol required estrogen receptor-β. The disruption of the intestinal microbial conversion of daidzein to equol abolished daidzein’s protective effect against aneurysm formation. Mice treated with equol had lower inflammatory cytokines in the cerebral arteries, suggesting that phytoestrogens modulate inflammatory processes important to intracranial aneurysm pathogenesis. Our study establishes that both dietary daidzein and its metabolite, equol, protect against aneurysm formation in ovariectomized female mice through the activation of estrogen receptor-β and subsequent suppression of inflammation. Dietary daidzein’s protective effect required the intestinal conversion to equol. Our results indicate the potential therapeutic value of dietary daidzein and its metabolite, equol, for the prevention of the formation of intracranial aneurysms and related subarachnoid hemorrhage.

Randomized Controlled Trial of Oral Vancomycin Treatment in Clostridioides difficile-Colonized Patients.

Clostridioides difficile infection (CDI) is most commonly diagnosed using nucleic acid amplification tests (NAAT); the low positive predictive value of these assays results in patients colonized with C. difficile unnecessarily receiving CDI treatment antibiotics. The risks and benefits of antibiotic treatment in individuals with such cases are unknown. Fecal samples of NAAT-positive, toxin enzyme immunoassay (EIA)-negative patients were collected before, during, and after randomization to vancomycin (n = 8) or placebo (n = 7). C. difficile and antibiotic-resistant organisms (AROs) were selectively cultured from fecal and environmental samples. Shotgun metagenomics and comparative isolate genomics were used to understand the impact of oral vancomycin on the microbiome and environmental contamination. Overall, 80% of placebo patients and 71% of vancomycin patients were colonized with C. difficile posttreatment. One person randomized to placebo subsequently received treatment for CDI. In the vancomycin-treated group, beta-diversity (P = 0.0059) and macrolide-lincosamide-streptogramin (MLS) resistance genes (P = 0.037) increased after treatment; C. difficile and vancomycin-resistant enterococci (VRE) environmental contamination was found in 53% of patients and 26% of patients, respectively. We found that vancomycin alters the gut microbiota, does not permanently clear C. difficile, and is associated with VRE colonization/environmental contamination. (This study has been registered at ClinicalTrials.gov under registration no. NCT03388268.)IMPORTANCE A gold standard diagnostic for Clostridioides difficile infection (CDI) does not exist. An area of controversy is how to manage patients whose stool tests positive by nucleic acid amplification tests but negative by toxin enzyme immunoassay. Existing data suggest most of these patients do not have CDI, but most are treated with oral vancomycin. Potential benefits to treatment include a decreased risk for adverse outcomes if the patient does have CDI and the potential to decrease C. difficile shedding/transmission. However, oral vancomycin perturbs the intestinal microbiota and promotes antibiotic-resistant organism colonization/transmission. We conducted a double-blinded randomized controlled trial to assess the risk-benefit of oral vancomycin treatment in this population. Oral vancomycin did not result in long-term clearance of C. difficile, perturbed the microbiota, and was associated with colonization/shedding of vancomycin-resistant enterococci. This work underscores the need to better understand this population of patients in the context of C. difficile/ARO-related outcomes and transmission.

Long-term oral vancomycin for refractory inflammatory bowel diseases without Clostridium difficile infection: Lessons from primary sclerosing cholangitis

Dysbiosis is a prominent feature of inflammatory bowel diseases (IBD). However, the efficacy of using antibiotics aiming at the aberrant gut microflora for IBD treatment are either unsuccessful or not persistent. In contrast, long-term oral vancomycin has been proved effective in controlling both the bile duct and gut inflammation of primary sclerosing cholangitis (PSC), an autoimmune disease against the intra- and extrahepatic bile ducts that holds a high rate of concomitant IBD and shares many common characteristics with IBD, including similar dysbiosis patterns. Two discrepancies of antibiotic usage might explain the dramatically different responses of the two diseases toward this strategy. First, the vast majority of antibiotic formulas for IBD management consist of broad-spectrum antibiotics mainly targeting gram-negative bacteria with some covering anaerobes and gram-positive ones, while vancomycin used for PSC treatment almost exclusively targets gram-positive bacteria. Several lines of clues suggested that gram-positive microorganisms might be responsible for the chronic inflammation observed in IBD and PSC. Second, improvement of liver test in PSC patients is usually observed after a relatively long period of oral vancomycin treatment (more than 12 weeks) and it takes even longer for gut mucosal healing. Moreover, long-term low dose oral vancomycin is required to prevent PSC recurrence. However, most trials of using antibiotics for IBD management is aiming at inducing remission with short treatment course (most less than 2 weeks) without maintenance. We hypothesize that the host antimicrobial response favors the growth of certain gram-positive intestinal bacteria in genetically predisposed individuals which is responsible for the aberrant immunological reaction towards the gut mucosa. Oral vancomycin induces disease remission by suppressing the pathogenic gram-positive microorganisms, but long course is needed since the gut inflammation is usually severe than that concomitant with PSC. Moreover, long-term maintenance is required to prevent the rebound of the pathogens and flare of the intestinal inflammation.

Optimal vancomycin dose in the treatment of Clostridium difficile infection, antimicrobial stewardship initiative

C. difficile infections (CDI) are increasingly recognized as a leading cause of infectious diarrhea, with increasing morbidity and mortality. Treatment primarily centers around oral vancomycin treatment. A wide range of dosing regimens exist in clinical practice, with little evidence to help distinguish the therapeutic benefit between them. This is a retrospective cohort study conducted at an academic medical center that enrolled adult patients admitted with CDI. The primary outcome was a composite of complete or partial cure at the end of treatment and was assessed using a test of equivalency with a 20% equivalency limit. Subjects were divided into low dose (125 mg) or high dose (250 mg or 500 mg) of oral vancomycin dosed every 6 hours. Overall, 78 patients were included who received low dose vancomycin and 33 who received high dose. Generally, the two groups were similar, except the low dose group had significantly more leukocytosis and less ICU admission or hypotension compared to the high dose group. Equivalency between the two treatment groups was demonstrated (Absolute Risk Difference −0.022, 90% confidence interval: −0.13 to 0.18, p = 0.03). A stepwise logistic regression identified gender, baseline albumin, and ICU admission as significant predictors of the chance for complete or partial cure. No differences between groups for the secondary outcomes of 90-day readmission/recurrence, 30-day all-cause mortality, or time to resolution of diarrhea were demonstrated. Low dose oral vancomycin was demonstrated to result in equivalent outcomes compared to high dose vancomycin for the treatment of CDI.

Open-label prospective therapeutic clinical trials: oral vancomycin in children and adults with primary sclerosing cholangitis

Background Oral vancomycin (OV) in primary sclerosing cholangitis (PSC) has been evaluated as a potential therapeutic agent. We report the long-term biochemical course and outcomes of patients with PSC treated with OV. Methods Patients were enrolled in 2 open-label clinical trials (ClinicalTrials.gov Identifier: NCT01802073 and NCT01322386) and offered OV at 50 mg/kg/day in 3 divided doses if weight <30kg, and 500 mg 3 times/day if weight ≥30kg. Patients with biliary strictures requiring stenting or awaiting liver transplant were excluded. Liver biochemistry, MRCP and histology were documented at baseline and while on OV. The primary outcome was a decrease in elevated gamma glutamyl transferase (GGT), alkaline phosphatase (ALP), and/or alanine aminotransferase (ALT) from baseline. Results 30 subjects were enrolled, and 29 additional subjects who learned of the clinical trial requested OV (total n = 59; median age was 13.5 years [range, 1.5–44 years]; 64.4% were male; and 94.9% had inflammatory bowel disease [IBD]). The median treatment duration was 2.7 years (range, 0.2–14 years). Ninety-six percent (57/59), 81.3% (48/59), and 94.9% (56/59) experienced reduction of GGT, ALP, and ALT, respectively. Furthermore, 39% (23/59), 22% (13/59), and 55.9% (33/59) experienced normalization of GGT, ALP, and ALT, respectively, within the first 6 months of OV treatment. One patient underwent liver transplantation 8 years after beginning OV treatment, and one developed biliary strictures requiring endoscopic intervention. OV was well-tolerated by patients, and no patient developed treatment-related adverse events. Conclusion In PSC, OV was well-tolerated and was associated with improvement in liver chemistry. A randomized placebo-controlled clinical trial is warranted.

Universal molecular Clostridioides difficile screening and overtreatment in solid organ transplant recipients.

Screening for Clostridioides difficile (CD) colonization can be performed using molecular testing to identify the presence of microbial DNA of the toxin gene. Colonization rates for hospitalized patients are as high as 20% and may be considerably higher in solid organ transplant (SOT) recipients. Treatment for CD should be based on clinical disease and not colonization, yet clinicians may misinterpret a positive CD screen resulting in overtreatment. The objective of this analysis is to determine how often positive CD screens resulted in inappropriate treatment with oral vancomycin. Clostridioides difficile screens were performed using the XpertCdifficileassay (Cepheid), a nucleic acid amplification testing method utilizing polymerase chain reaction (PCR), on peri-rectal swabs for newly admitted patients. This was a single-center cohort study of adult patients with CD screens hospitalized between July 2015 and November 2018. The primary outcome was the rate of inappropriate oral vancomycin treatment in all patients and in SOT recipients, defined as therapy in the absence of diarrhea. Of the 47076 total CD screens reviewed, 1,921 were positive. In the SOT cohort, 58 of 329 screens were positive (4.1% vs 17.9%, P<.01). Of all patients with a positive CD screen, 20.1% (386/1921) were treated with oral vancomycin within 48hours of swab collection. In the SOT cohort, 39.6% (23/58) with positive CD screens were treated with oral vancomycin within 48hours. Of the SOT patients who received oral vancomycin, 39% (9/23) did not have true CD infection. Solid organ transplant recipients were more likely to have CD colonization detected by peri-rectal screening than the general inpatient population. SOT and non-SOT patients were treated with oral vancomycin at similar rates in response to the positive screen. Nearly half of the oral vancomycin use in SOT recipients was likely overtreatment, but this finding is limited by the low number of patients in this cohort.

Effects of underfeeding and oral vancomycin on gut microbiome and nutrient absorption in humans.

Direct evidence in humans for the impact of the microbiome on nutrient absorption is lacking. We conducted an extended inpatient study using two interventions that we hypothesized would alter the gut microbiome and nutrient absorption. In each, stool calorie loss, a direct proxy of nutrient absorption, was measured. The first phase was a randomized cross-over dietary intervention in which all participants underwent in random order 3 d of over- and underfeeding. The second was a randomized, double-blind, placebo-controlled pharmacologic intervention using oral vancomycin or matching placebo (NCT02037295). Twenty-seven volunteers (17 men and 10 women, age 35.1 ± 7.3, BMI 32.3 ± 8.0), who were healthy other than having impaired glucose tolerance and obesity, were enrolled and 25 completed the entire trial. The primary endpoints were the effects of dietary and pharmacological intervention on stool calorie loss. We hypothesized that stool calories expressed as percentage of caloric intake would increase with underfeeding compared with overfeeding and increase during oral vancomycin treatment. Both primary endpoints were met. Greater stool calorie loss was observed during underfeeding relative to overfeeding and during vancomycin treatment compared with placebo. Key secondary endpoints were to evaluate the changes in gut microbial community structure as evidenced by amplicon sequencing and metagenomics. We observed only a modest perturbation of gut microbial community structure with under- versus overfeeding but a more widespread change in community structure with reduced diversity with oral vancomycin. Increase in Akkermansia muciniphila was common to both interventions that resulted in greater stool calorie loss. These results indicate that nutrient absorption is sensitive to environmental perturbations and support the translational relevance of preclinical models demonstrating a possible causal role for the gut microbiome in dietary energy harvest.

Clostridioides difficile associated peritonitis in peritoneal dialysis patients \u2013 a case series based review of an under-recognized entity with therapeutic challenges

BackgroundInitial presentation of peritoneal dialysis associated infectious peritonitis can be clinically indistinguishable from Clostridioides difficile infection (CDI) and both may demonstrate a cloudy dialysate. Empiric treatment of the former entails use of 3rd-generation cephalosporins, which could worsen CDI. We present a logical management approach of this clinical scenario providing examples of two cases with CDI associated peritonitis of varying severity where the initial picture was concerning for peritonitis and treatment for CDI resulted in successful cure.Case presentationA 73-year-old male with ESRD managed with PD presented with fever, abdominal pain, leukocytosis and significant diarrhea. Cell count of the peritoneal dialysis effluent revealed 1050 WBCs/mm3 with 71% neutrophils. C. difficile PCR on the stool was positive. Patient was started on intra-peritoneal (IP) cefepime and vancomycin for treatment of the peritonitis and intravenous (IV) metronidazole and oral vancomycin for treatment of the C. difficile colitis but worsened. PD fluid culture showed no growth. He responded well to IV tigecycline, oral vancomycin and vancomycin enemas. Similarly, a 55-year-old male with ESRD with PD developed acute diarrhea and on the third day noted a cloudy effluent from his dialysis catheter. PD fluid analysis showed 1450 WBCs/mm3 with 49% neutrophils. IP cefepime and vancomycin were initiated. CT of the abdomen showed rectosigmoid colitis. C. difficile PCR on the stool was positive. IP cefepime and vancomycin were promptly discontinued. Treatment with oral vancomycin 125 mg every six hours and IV Tigecycline was initiated. PD fluid culture produced no growth. PD catheter was retained.ConclusionsIn patients presenting with diarrhea with risk factors for CDI, traditional empiric treatment of PD peritonitis may need to be reexamined as they could have detrimental effects on CDI course and patient outcomes.

Comparative Effectiveness of Vancomycin and Metronidazole for the Initial Episode of Nonsevere Clostridium Difficle Infection

The infection with Clostridium difficile (CDI), which appeared at epidemic level, after acquiring the germ of some fluoroquinolone resistance genes, initially considered nosocomial infection and adverse effect post-antibiotic therapy, is affecting more and more people without risk factors and extending into the community. This paper proposes an analysis of the two main antibiotics used in therapy: metronidazole and vancomycin, the evidence of efficacy in the literature and the chemical stability of antibiotics in simulated gastrointestinal fluid. Based on UV-Vis absorption spectra, it can be considered that there are no major changes in the chemical structure of the investigated drugs in the presence of gastro-duodenal conditions. Clinical impact of comparative treatment with metronidazole and vancomycin has also been studied, in a group of 720 CDI patients hospitalized during the period 1.01.2017-31.12.2018 in the Clinical Hospital St. Parascheva of Infectious Diseases Galati. From this group, two subgroups were selected, one of 284 patients receiving oral vancomycin treatment and one group of 62 patients receiving oral metronidazole for an initial nonsevere episode of CDI. The number of days from the beginning of the treatment until the normalization of the stool, the length of hospitalization, the number of days of antibiotic treatment and the percentage of relapses were comparable in the two groups, the percentage of deaths in the first 30 days from the episode of CDI was higher in the vancomycin-treated group, probably due mainly to the severe comorbidities of these patients. The conclusion of the study is that the treatments with metronidazole and vancomycin, of the initial episode, nonsevere of CDI are comparable as a therapeutic response, provided that the patients treated with metronidazole do not associate hepatic, renal or neurological impairment due to the risk of adverse reactions.

Comparative Effectiveness of Vancomycin and Metronidazole for the Initial Episode of Nonsevere Clostridium Difficle Infection

The infection with Clostridium difficile (CDI), which appeared at epidemic level, after acquiring the germ of some fluoroquinolone resistance genes, initially considered nosocomial infection and adverse effect post-antibiotic therapy, is affecting more and more people without risk factors and extending into the community. This paper proposes an analysis of the two main antibiotics used in therapy: metronidazole and vancomycin, the evidence of efficacy in the literature and the chemical stability of antibiotics in simulated gastrointestinal fluid. Based on UV-Vis absorption spectra, it can be considered that there are no major changes in the chemical structure of the investigated drugs in the presence of gastro-duodenal conditions. Clinical impact of comparative treatment with metronidazole and vancomycin has also been studied, in a group of 720 CDI patients hospitalized during the period 1.01.2017-31.12.2018 in the Clinical Hospital St. Parascheva of Infectious Diseases Galati. From this group, two subgroups were selected, one of 284 patients receiving oral vancomycin treatment and one group of 62 patients receiving oral metronidazole for an initial nonsevere episode of CDI. The number of days from the beginning of the treatment until the normalization of the stool, the length of hospitalization, the number of days of antibiotic treatment and the percentage of relapses were comparable in the two groups, the percentage of deaths in the first 30 days from the episode of CDI was higher in the vancomycin-treated group, probably due mainly to the severe comorbidities of these patients. The conclusion of the study is that the treatments with metronidazole and vancomycin, of the initial episode, nonsevere of CDI are comparable as a therapeutic response, provided that the patients treated with metronidazole do not associate hepatic, renal or neurological impairment due to the risk of adverse reactions. Keywords: Clostridium difficile, metronidazole, vancomycine, chemical stability, UV-Vis spectra

Does oral vancomycin use necessitate therapeutic drug monitoring?

Oral vancomycin use has generally increased as a consequence of the need to treat and/or prevent Clostridium (Clostridiodes) difficile-associated disease (CDAD). This review examines the cumulative scientific evidence that guides therapeutic monitoring of oral vancomycin therapy. The existing publications were reviewed from the time of the drug's inception to July 2019. This review utilized access as available in PubMed, EMBASE, CINAHL Plus, and the Cochrane Library. Case reports and small patient series have documented anecdotal-associated elevations in serum levels. Correlation of absorbed vancomycin with subsequent toxicity is difficult to determine, but serum levels approaching those obtained after parenteral administration have raised concern. Prolonged usage and total dosing over 500mg/day among adult age ranges have been associated with accumulation. In addition, risk factors for vancomycin accumulation systemically after oral dosing include renal compromise, combined oral and other enteral therapy, severe CDAD, other intercurrent bowel inflammation, polypharmacy, and increased patient complexity/morbidity. Until systemic toxicity from oral vancomycin absorption is better understood, individual considerations should be made for therapeutic serum monitoring during oral vancomycin treatment. Therapeutic drug monitoring is suggested for several high-risk situations in which high blood levels may be anticipated.