Difficile Antibiotic Research Articles

The Novel DNA Binding Mechanism of Ridinilazole, a Precision Clostridiodes difficile Antibiotic.

Clostridioides difficile infection (CDI) causes substantial morbidity and mortality worldwide with limited antibiotic treatment options. Ridinilazole is a precision bisbenzimidazole antibiotic being developed to treat CDI and reduce unacceptably high rates of infection recurrence in patients. Although in late clinical development, the precise mechanism of action by which ridinilazole elicits its bactericidal activity has remained elusive. Here, we present conclusive biochemical and structural data to demonstrate that ridinilazole has a primary DNA binding mechanism, with a co-complex structure confirming binding to the DNA minor groove. Additional RNA-seq data indicated early pleiotropic changes to transcription, with broad effects on multiple C. difficile compartments and significant effects on energy generation pathways particularly. DNA binding and genomic localization was confirmed through confocal microscopy utilizing the intrinsic fluorescence of ridinilazole upon DNA binding. As such, ridinilazole has the potential to be the first antibiotic approved with a DNA minor groove binding mechanism of action.

Fidaxomicin monotherapy versus standard therapy combined with bezlotoxumab for treating patients with Clostridioides difficile infection at high risk of recurrence: a matched cohort study.

Both fidaxomicin and bezlotoxumab (used in combination with an antibiotic against Clostridioides difficile) achieve reductions in recurrence rates of C. difficile infection (CDI). However, the two strategies have never been compared. Data from two retrospective cohorts of 'real-life' use of fidaxomicin and bezlotoxumab in combination with a standard anti-C. difficile antibiotic were used to compare the rates of recurrence of both strategies. Since the two cohorts were not identical, we used a propensity score analysis. Three hundred and two patients were included: 244 in the fidaxomicin cohort and 78 in the bezlotoxumab cohort. A history of renal failure or immunosuppression was more frequent in patients receiving bezlotoxumab (39.7% and 66.7% versus 26.6% and 38.9%; P = 0.03 and P < 0.001, respectively), but the severity and number of previous CDI episodes were similar in both cohorts. We observed that 19.3% of the patients in the fidaxomicin cohort experienced recurrence, compared with 14.1% in the bezlotoxumab cohort (OR 1.45; 95% CI 0.71-2.96; P = 0.29) but the difference remained non-significant after propensity score matching using previously defined variables (OR 1.24; 95% CI 0.50-3.07; P = 0.64). Moreover, the multivariate analysis did not show differences depending on the drug used. We observed that fidaxomicin and bezlotoxumab are prescribed in similar clinical scenarios, although those treated with bezlotoxumab have greater comorbidity. The proportion of recurrences was numerically lower in those treated with bezlotoxumab, although the propensity analysis did not find significant differences between the two drugs.

Correlation between antibiotic consumption and the incidence of healthcare facility-onset Clostridioides difficile infection: a retrospective chart review and analysis

BackgroundHealthcare facility-onset Clostridioides difficile infection is the leading cause of antibiotic-associated diarrhea, and is associated with morbidity and mortality. The use of antibiotics is an important risk factor for healthcare facility-onset C. difficile infection. We evaluated the correlation between the incidence of healthcare facility-onset C. difficile infection and antibiotic consumption, according to antibiotic class.MethodsPatients with healthcare facility-onset C. difficile infection from January 2017 to December 2018 at Konkuk University Medical Center (a tertiary medical center) were included. We evaluated changes in the incidence of healthcare facility-onset C. difficile infection and antibiotic consumption. The correlation between the incidence of healthcare facility-onset C. difficile infection and antibiotic consumption was evaluated two ways: without a time interval and with 1-month interval matching.ResultsA total of 446 episodes of healthcare facility-onset C. difficile infection occurred during the study period. The incidence of healthcare facility-onset C. difficile infection was 9.3 episodes per 10,000 patient-days, and increased significantly. We observed an increase in the consumption of β-lactam/β-lactamase inhibitors, and a decrease in the consumption of other classes of antibiotics, with a significant decrease in the consumption of fluoroquinolones, glycopeptides, and clindamycin (P = 0.01, P < 0.001, and P = 0.001, respectively). The consumption of β-lactam/β-lactamase inhibitors was independently correlated with the incidence of healthcare facility-onset C. difficile infection in the analysis without a time interval. When the analysis was conducted with 1-month interval matching, glycopeptide consumption was independently associated with the incidence of healthcare facility-onset C. difficile infection.ConclusionsDespite the reduction in fluoroquinolone and clindamycin consumption, the incidence of healthcare facility-onset C. difficile infection increased during the study period, and was correlated with increased consumption of β-lactam/β-lactamase inhibitors. Reduced consumption of specific antibiotics may be insufficient to reduce the incidence of healthcare facility-onset C. difficile infection.

786. Diagnostic stewardship of C difficile PCR testing with two step algorithm- A rural community hospital experience

BackgroundAn estimated 15% of hospitalized patients are asymptomatic carriers of C. diff. Inappropriate testing can lead to over diagnosis, treatment, isolation & substantial financial penalties. Ours is a rural 310 bed hospital with nurse driven C. diff test ordering protocol. Due to inadvertent test ordering, we had an uptick in the HO-CDI incidence with rates as high as 0.94 per 1000 patient days in 2017. In order to streamline testing, we initiated an infection preventionist(IP) led diagnostic stewardship program which was implemented in two phases in 2017-2019MethodsThe phase 1 involved daily review by IPs regarding the legitimacy of PCR order for minimum 3 loose stools in 24 hours, use of laxatives, presence of symptoms.There were concerns nationally that then CDI risk adjustment model from NHSN in 2017 does not optimally account for the impact of specific CDI testing methods used by individual hospitals on CDI SIRs. Hence, in Jan 2018 NHSN’s MDRO/CDI Protocol stated “Results of the final test that are placed in the patient’s medical record should be used to determine whether event meets the CDI LabID defn”.This led to phase 2 in mar 2019 which involved two step testing which started with C diff PCR assay with positive test reflexed to the toxin A/B assay.ResultsDuring the first phase, and a full year of the protocol in 2018, the number of completed PCR tests decreased to 626 (compared to 940 PCR tests in 2016) with an 34% decrease. In the year following implementation of the Diagnostic Stewardship, HO CDI decreased from 60 in 2017 to 43 events in 2018 with a reduction of 28%. Subsequently, HO CDI further decreased in 2019 to 28 with a reduction of 35%. Since the start of the project in 2017, HO CDI have decreased 54% in total. The reduction in 314 C diff PCR tests in the first year[2017-2018] led to a savings of $8300 in lab supplies. No readmissions with C difficile infection documented within 30 days on patients who did not meet the criterion for testing. Significant decrease in the usage of C difficile antibiotics. After the start of the two step test, we have seen a precipitous drop in our HO-CDI rates to less than 0.3 per 1000 pt days by the end of 2019.Quarterly comparison of HO CDI incidence for 2017-2020 HO CDI incidence before and following phase 1 and phase 2 interventions C. difficile antibiotic use trends during intervention period ConclusionIP run diagnostic stewardship programs with two step tests are highly successful in streamlining testing and in discriminating infection from colonizationDisclosures All Authors: No reported disclosures

2363. Implementation of a Multi-Step Diagnostic Algorithm for C. difficile Infection

BackgroundThe diagnosis of C. difficile infection (CDI) in the hospital is challenging asymptomatic colonization rates vary between 3% and 26%. Guidelines recommend multistep testing for CDI diagnosis. On July 1, 2018 a two-step testing algorithm was implemented at our institution. Positive nucleic acid amplification test (NAAT) results reflexed to a toxin enzyme immunoassay (EIA) test. The EIA test result was then used for NHSN reporting; however, both test results were visible to the clinician. Updated guidance on the interpretation of the test and treatment of CDI was released to the medical staff in July. We compared the incidence of CDI lab ID events per 1000 patient-days and the rate of C. difficile antibiotic starts before and after the implementation of the testing algorithm.MethodsA retrospective observational study was performed at an 800 bed regional medical center. CDI lab ID events between January 1 and December 31, 2018 were reviewed. Antibiotic initiation of intravenous (IV) and oral (PO) metronidazole and PO vancomycin was collected for all hospitalized patients diagnosed with C. difficile. The incidence of hospital onset (HO) and community-onset (CO) lab ID events as well as the rate of antibiotic starts were compared before and after implementation of the algorithm using a two-sided z test for proportions with an alpha of 0.05.ResultsThe incidence of HO and CO lab ID events per 1000 patient-days decreased significantly from 0.56 to 0.16 (P < 0.0001) and 1.18 to 0.3 (P < 0.0001) after implementation of the testing algorithm (Figure 1). The CDI SIR decreased from 0.729 to 0.322, (P = 0.0048). The rate of antibiotic starts per 1,000 patient-days for IV and PO Metronidazole decreased significantly from 1.1 to 0.45 (P < 0.0001) and 0.86 to 0.35 (P < 0.0001), respectively. PO Vancomycinstarts decreased from 1.51 to 1.23 (P = 0.11) (Table 1).ConclusionA two-step algorithm for diagnosing CDI decreases the overall number of HO and CO C. difficile lab ID events and decreases overall antimicrobial use for CDI. Disclosures All authors: No reported disclosures.

Risk factors for recurrent Clostridium difficile infection in a tertiary hospital in Israel.

To estimate the rate and identified risk factors for recurrent Clostridium difficile infection (rCDI) in Israel. We conducted a retro-prospective case-control study of all adult (age ≥ 18years) patients with an initial episode of CDI (iCDI) at Tel Aviv Sourasky Medical Center from January 1, 2012 to December 31, 2014. We collected demographic, clinical, and epidemiological information for patients who were classified as recurrent (cases) and non-recurrent (control) groups. In total, 648 patients with iCDI were identified in the study. During the 36-month study period, 82 (12.7%) patients had at least one rCDI identified. We identified several factors as independent variables significantly associated with recurrent CDI: functional disability, severity of the initial infection, continuous non-Clostridium difficile antibiotic treatment with third-generation cephalosporins or clindamycin, and iCDI treatment with metronidazole and vancomycin; however, neutropenia had high measure of effect as a predictor for rCDI (adjusted odds ratio, 7.9; 95% confidence interval, 1.27-49.58; p = 0.026). The identification of the main modifiable risk factors for recurrent CDI, continuous non-Clostridium difficile antibiotics after diagnosis of the initial infection, and antibiotic treatment with third-generation cephalosporins or clindamycin are critical in reducing the spread of recurrent infection with Clostridium difficile in hospital.

Collateral damage during antibiotic treatment of C. difficile infection in the aged host: Insights into why recurrent disease happens

ABSTRACTClostridium difficile infection (CDI) is one of the most common causes of healthcare-associated infections but an even bigger problem for the aging population. Advanced age leads to higher incidence, higher mortality, and higher recurrences. In our study, recently published in the Journal of Infectious Diseases, we investigated the effect of aging on CDI using a mouse model. We were able to demonstrate that aging leads to worse clinical outcomes, as well as lead to changes in microbiota composition and lower antibody production against C. difficile toxin A, but not toxin B. An association between advanced age and lower antibody production against C. difficile is a new finding which would explain the effect of aging on CDI outcome. Vancomycin, an anti-C. difficile antibiotic, led to similar changes in antibody response, suggesting a connection between microbiome and antibody response in the context of aging, which would require a much more nuanced look at the treatment of CDI.

Tu2020 Persistent Colonic Mucosal Epigenetic Changes in Pediatric Ulcerative Colitis

G A A b st ra ct s benefit from C. difficile directed antibiotic therapies prior to FMT. These patients responded well to a single FMT. The UC patient required FMT 3 times to clear CDI, but still received colectomy during his subsequent clinical course. The CD patient's diarrhea did not respond to either antibiotics or FMT. One patient was diagnosed with poorly managed constipation and C. difficile carriage during her 2nd enema FMT. CONCLUSIONS: FMT is highly effective for the treatment of pediatric rCDI in patients without complicating clinical conditions. Clinical improvement during C. difficile directed antibiotic therapy in the course of rCDI indicates a favorable outcome following FMT. FMT results in engraftment of donor bacterial species and reconstitution of recipient microbiomes. Asymptomatic C. difficile carriage may predispose to CDI. A special approach, incorporating these findings, should be made towards pediatric rCDI patients with underlying disorders when considering FMT.

Clostridium difficile drug pipeline: challenges in discovery and development of new agents.

In the past decade Clostridium difficile has become a bacterial pathogen of global significance. Epidemic strains have spread throughout hospitals, while community acquired infections and other sources ensure a constant inoculation of spores into hospitals. In response to the increasing medical burden, a new C. difficile antibiotic, fidaxomicin, was approved in 2011 for the treatment of C. difficile-associated diarrhea. Rudimentary fecal transplants are also being trialed as effective treatments. Despite these advances, therapies that are more effective against C. difficile spores and less damaging to the resident gastrointestinal microbiome and that reduce recurrent disease are still desperately needed. However, bringing a new treatment for C. difficile infection to market involves particular challenges. This review covers the current drug discovery pipeline, including both small molecule and biologic therapies, and highlights the challenges associated with in vitro and in vivo models of C. difficile infection for drug screening and lead optimization.

P703 A prospective study on Clostridium difficile infection, toxino type and antibiotic sensitivity in inflammatory bowel disease

P703 A prospective study on Clostridium difficile infection, toxino type and antibiotic sensitivity in inflammatory bowel disease

C. difficile Antibiotic Promising in Early Trial

C. difficile Antibiotic Promising in Early Trial

Optimer resurrects C. difficile antibiotic to win approval

Optimer resurrects C. difficile antibiotic to win approval

Phase III success for novel Clostridium difficile antibiotic

Phase III success for novel Clostridium difficile antibiotic

Bovine immunoglobulin concentrate-Clostridium difficile retains C difficile toxin neutralising activity after passage through the human stomach and small intestine

BackgroundBovine immunoglobulin concentrate (BIC)-Clostridium difficile is prepared from the colostrum of cows immunised againstC difficile toxins and contains high concentrations of neutralising IgG antitoxin.AimsTo determine the proportion of BIC-C difficile...