bluuebunny/crossref_metadata_2025 huggingface dataset:
Activity of Ceftazidime–Avibactam Against Respiratory Isolates of Enterobacteriaceae and Pseudomonas aeruginosa Collected in Asia/Pacific as part of the INFORM Global Surveillance Program, 2014–2016
Authors: Kazmierczak Krystyna , Wise Mark , Stone Gregory G , Sahm Dan
Published: October 2017

Background

Avibactam (AVI) is a non-β-lactam β-lactamase inhibitor that restores the in vitro activity of ceftazidime (CAZ) against class A, class C, and some class D β-lactamases, including extended-spectrum β-lactamases, serine carbapenemases, and the chromosomal AmpC of Pseudomonas aeruginosa (Pae). This study evaluated the in vitro activity of CAZ-AVI and comparators against Enterobacteriaceae (Eba) and Pae collected from patients with lower respiratory tract infections (LRTI) in Asia/Pacific in 2014–2016 as part of the INFORM surveillance program.

Methods

Non-duplicate isolates from patients with LRTI were collected from 28 medical centers in Australia, Hong Kong, Japan, Malaysia, Philippines, South Korea, Taiwan, and Thailand. Susceptibility (S) testing was performed by broth microdilution and interpreted using FDA breakpoints for CAZ-AVI and CLSI breakpoints for comparators. AVI was tested at a fixed concentration of 4 µg/mL with doubling dilutions of CAZ. Multidrug resistance (MDR) phenotype was defined as resistant by CLSI breakpoints to sentinel agents from ≥3 drug classes.

Results

CAZ-AVI showed potent in vitro activity against the overall population of Eba (MIC90, 0.5 µg/mL; 98.0% S) and against ceftazidime-nonsusceptible (CAZ-NS), colistin-resistant (CST-R), and MDR isolates, with >91% of these resistant subsets testing as susceptible (MIC ≤8 µg/mL). Reduced activity against meropenem-nonsusceptible (MEM-NS) Eba was attributable to the presence of class B metallo-β-lactamases (MBL); 95.7% of MEM-NS, MBL-negative isolates were susceptible to CAZ-AVI. CAZ-AVI also showed good activity against most Pae isolates (MIC90, 8 µg/mL; 92.5% S), as well as CST-R isolates (MIC90, 8 µg/mL; 100% S). Activity of CAZ-AVI was reduced against CAZ-NS, MEM-NS, MEM-NS MBL-negative, and MDR Pae subsets (46.9–82.3% S) but exceeded the activity of CAZ and MEM.

Conclusion

CAZ-AVI is a potential therapeutic option for treating respiratory infections in the Asia/Pacific region caused by Eba and Pae isolates resistant to commonly used and last-in-line agents.

Disclosures

G. G. Stone, Pfizer: Employee, Salary AstraZeneca: Shareholder, Capital Gains
Activity of Ceftolozane-Tazobactam Against Global Pseudomonas Aeruginosa and Non-Susceptible Phenotypes: SMART 2016
Authors: Lob Sibylle , Hackel Meredith , Badal Robert , Young Katherine , Motyl Mary , Sahm Dan
Published: October 2017

Background

Pseudomonas aeruginosa (PA), one of the species of the ESKAPE pathogens that are known to “escape” the effects of many antimicrobials, is often difficult to treat. Ceftolozane-tazobactam (C/T) is an anti-pseudomonal cephalosporin/β-lactamase inhibitor recently approved by FDA and EMEA. We examined its activity against global clinical isolates of PA, including isolates non-susceptible (NS, intermediate or resistant) to other agents.

Methods

In 2016, 158 hospitals in 51 countries collected 5533 PA from intra-abdominal (IAI), urinary (UTI), and respiratory tract infections (RTI). MICs were determined using CLSI broth microdilution and interpreted with both CLSI and EUCAST breakpoints, as the susceptible breakpoints for C/T, cefepime (FEP), meropenem (MEM), and piperacillin-tazobactam (P/T) are the same using both criteria.

Results

Overall regional susceptibility of PA to C/T, prevalence of FEP-NS, MEM- NS, and P/T- NS phenotypes, and susceptibility of these phenotypes to C/T are shown below:

Conclusion

Overall susceptibility to C/T ranged from 85% in Latin America to 98% in South Pacific. FEP-NS, MEM-NS, and P/T-NS isolates were least prevalent in South Pacific. C/T was active against these phenotypes in >80% of isolates in North America and South Pacific and against 62–73% of MEM-NS and P/T-NS isolates in all other regions except Latin America. Monitoring of C/T susceptibility to PA is warranted in light of increasing resistance to first line agents.

Disclosures

M. Hackel, IHMA: Employee, Salary; R. Badal, IHMA, Inc: Employee, Salary; K. Young, Merck: Employee and Shareholder, Dividends and Salary M. Motyl, Merck & Co., Inc.,: Employee, Salary
Engraftment and Augmentation of Microbiome Following Fecal Microbiota Transplantation for Recurrent Clostridium difficile Infection
Authors: Lee Christine , Rush Stephen , Weese J Scott , Goldeh Peyman , Kim Peter
Published: October 2017

Background

Recurrent Clostridum diffcile infection (rCDI) poses major challenges to healthcare providers and patients. Fecal Microbiota Transplantation (FMT) is an effective therapy for rCDI, but the exact mechanism of its efficacy is unknown. Current metagenomics literature indicates that abundance of Bacteroidetes and Firmicutes may protect against CD proliferation and recurrence. However, this is too broad to be useful for developing refined and targeted microbial-specific therapy for rCDI, because the long-term safety of FMT remains unknown. We examined the phylogeny of bacteria pre- and post- FMT to determine the key organisms associated with successful FMT to the genera level.

Methods

A subset of patient stool samples (n = 35) from a phase 2 study comparing fresh vs. frozen FMT for rCDI was sequenced at four time points: pre-FMT; at day 10; at week 5; and at week 13, following the last FMT. The matching donor stool was sequenced simultaneously with the corresponding patients’ pre- and post-FMT samples.

Using the binary outcome to a single FMT as the response, we have developed an in-house machine learning algorithm, Φ-LASSO, to isolate key genera using the bacterial phylogenetic structure.

Engraftment was defined as: newly detected operational taxonomic unit (OTUs) in the patient post-FMT, which were present in the donor but undetected in the patient pre-FMT. Augmentation was defined as: non-donor OTUs whose levels substantially increased post-FMT. Figure 1 (below) displays the distribution of engrafted and augmented OTUs at varying thresholds. We observed increases over time points within each threshold level.

Results

Akkermansia, Blautia and Roseburiaappear to be key genera for successful FMT. The Φ-LASSO fits with consistently positive coefficients, see Figure 2.

Conclusion

In this preliminary study, using Φ-LASSO, we have shown that specific microbes to the genera level are uniformly present in successful FMT. This information may lead to developing refined and targeted microbial-therapy for rCDI.

Figure 1

Observed (a) engraftment of distinct donor OTUs on patients and (b) augmentation of distinct OTUs in patients for day 10 (D10), week 5 (W5), and week 13 (W13) post-treatment.

Figure 2

Fitted coefficients for donor OTUs selected by Φ-LASSO.

Disclosures

All authors: No reported disclosures.
Prospective, Open-label Trial to Evaluate Efficacy of Lyophilized Fecal Microbiota Transplantation for Treatment of Recurrent C. difficile Infection
Authors: Goldeh Peyman , Kim Peter , Abouanaser Salaheddin , Partlow Eric , Beckett Patricia , Onishi Catherine , Smieja Marek , Lee Christine
Published: October 2017

Background

Fecal microbiota transplantation (FMT) has shown to be effective for recurrent Clostridium difficile infection (rCDI). However, significant laboratory costs for donor screening and a lack of suitable donors and laboratory facility have restricted the availability of the treatment. In order to expand access to FMT, we have investigated the efficacy of lyophilized FMT, comparing it to the published historical efficacy of frozen FMT in preventing further episodes of CDI in patients with a history of rCDI. This study was designed to be open-labeled to expedite and minimize costs associated with conducting a two-armed randomized controlled trial, given that the efficacy of frozen FMT is known to be 85%. Additionally, using lyophilized FMT offers two major advantages: 1) its prolonged shelf life reduces cost because fewer donors need to be screened; and 2) it can be transported without freezing.

Methods

This is an open-labeled, prospective study involving 50 patients with a history of 2 or more rCDI who have failed at least 1 course of tapered vancomycin therapy. Eligible patients received 2 lyophilized FMT via retention enema within 8 days of each treatment and were followed for 13 weeks post last FMT to determine efficacy and safety of FMT.

Results

The efficacy of lyophilized FMTs in preventing further episodes of CDI in patients with rCDI was 80%. The adverse events associated with lyophilized FMT were similar to frozen FMT.

Conclusion

Lyophilized FMT in treating rCDI showed similar efficacy and safety to frozen FMT. Lyophilized FMT appears to be promising in preventing further episode of CDI and increasing accessibility for patients with rCDI.

Disclosures

All authors: No reported disclosures.
Efficacy of Oral Vancomycin, Oral Metronidazole, or IV Metronidazole Prophylaxis at Reducing the Risk of Clostridium difficile Recurrence
Authors: O’Connell Matthew , Slish Judianne , Shelly Mark
Published: October 2017

Background

Secondary prophylaxis (SP) for Clostridium difficile infection (CDI) with oral vancomycin or oral/IV metronidazole when initiating antibiotics is common, though few studies are available to support this practice. The purpose of this study was to assess the efficacy of prophylaxis within a year of index CDI.

Methods

This retrospective chart review looks at subsequent courses of antibiotics and CDI in patients with initial positive CDI testing in 2013–16. A positive CDI test within 90 days of antibiotics was a recurrence. The use of antibiotics for SP was noted, along with other factors associated with CDI relapse. Non-parametric and exact tests were used for univariate analysis. These variables were included in a multivariate proportional hazards model.

Results

We found 597 antibiotic episodes in 230 patients. 130 episodes (21.8%) received SP. The difference of recurrence rates with and without antibiotics, 9.2 % vs 10.7%, was not statistically significant. No difference was seen when metronidazole was used, but vancomycin SP reduced the rate to 7.5% (6/80, P = 0.45). Probiotics were associated with a higher rate of recurrence (16.7 vs. 8.9%, P = 0.025). Proton pump inhibitors were also associated with a slightly higher rate of CDI recurrence (13.0% vs. 8.4%). The rate of relapse fell significantly with increasing time since the index case of CDI by logistic regression (P = 0.011). In multivariate regression, relapse was associated with shorter time from index CDI, shorter durations of antibiotics, and the use of probiotics.

Conclusion

This retrospective study does not support the routine use of metronidazole in subsequent antibiotic courses following CDI. The use of probiotics paradoxically increased the rate of CDI relapse in this study. The limitations of this retrospective study do not eliminate the possibility of utility of vancomycin as prophylaxis, but this requires further evaluation.

Disclosures

All authors: No reported disclosures.
Tetracyclines are Associated with a Reduced Risk of Clostridium difficile Infection: A Systematic Review and Meta-analysis
Authors: Tariq Raseen , Cho Janice , Kapoor Saloni , Orenstein Robert , Singh Siddharth , Pardi Darrell , Khanna Sahil
Published: October 2017

Background

Efforts towards antibiotic stewardship help reduce risk of Clostridium difficile infection (CDI) but there is a need to delineate antibiotic choices to reduce CDI risk. Tetracyclines may be associated with a low risk for CDI but the evidence is conflicting. We conducted a systematic review and meta-analysis to determine the relationship between tetracyclines use and CDI.

Methods

A systematic search of Medline, Embase, and Web of Science was performed from January 1978 up to December 2016 including studies assessing the association between tetracyclines and CDI; compared with other antibiotics; to assess the risk of CDI after exposure to tetracyclines vs. other antibiotics. Study quality was assessed using the Newcastle-Ottawa scale. Weighted summary estimates were calculated using generalized inverse variance with random-effects model using Review Manager version 5.3 (Cochran Inc).

Results

Six studies; 4 case control and 2 cohort studies reported the association of CDI with tetracyclines or other antibiotics prior to CDI including patients from 1993 to 2012. Meta-analysis of all studies using the random-effects model demonstrated that tetracyclines were associated with decreased risk of CDI compared with other antibiotics (OR, 0.62; 95% CI, 0.47–0.81; P = .0005). There was significant heterogeneity among the studies, with an I2 of 53% (Figure 1). No publication bias was seen.

Subgroup analysis of studies evaluating the risk of CDI with doxycycline only also demonstrated a decreased risk of CDI with doxycycline compared with other antibiotics (OR, 0.55; 95% CI, 0.40–0.75; P = 0.0002). A subgroup analysis based on CDI diagnosis definitions revealed a decreased risk of CDI with tetracyclines (OR, 0.59; 95% CI, 0.44–0.80; P = 0. 0006) in studies that used clinical definitions (presence of diarrhea with a positive stool test), but not among the studies that used ICD-9 codes for CDI diagnosis (OR, 0.95; 95% CI, 0.45–2.01; P = 0.90).

Conclusion

Tetracyclines are associated with a lower risk of developing CDI compared with other antibiotics. It is reasonable to use these over other antibiotics when appropriate (community acquired pneumonia, bronchitis, chlamydia, rickettsial or spirochetal infections) to reduce the risk of CDI.

Forest plot demonstrating decreased odds of CDI with tetracyclines use by a random-effects model

Disclosures

All authors: No reported disclosures.
Clinical and Economic Evaluation of commercialized Fecal Microbiota Transplant (cFMT) for Patients with Recurrent Clostridium difficile Infection (CDI) in a Large Community Hospital
Authors: Hassoun Ali , Edwards Jonathan , Boyett Brian
Published: October 2017

Background

Recurrent CDI is common despite antibiotic therapy. FMT is effective to reduce recurrent infections. We report our experience with Commercialized FMT (cFMT) products by providing ready-to-use capsules, for oral administration, or solution, for administration via colonoscopy.

Methods

The study was approved by IRB for adult patients with at least 3 episode of recurrent CDI despite antibiotic therapy, patients with severe infection were excluded. cFMT was administered in the hospital or at outpatient center. Each patient was evaluated 8 weeks post-transplant to assess for sustained clinical cure and side effects. The economic impact of cFMT was evaluated using historical data from EHR including: CDI rate, CDI readmission rate, rate of CDI-associated death, cost of CDI admissions, and rate of use of each antimicrobial regimen

Results

33 patients enrolled (solution/colonoscopy 20 and capsule 13). Mean age was 74 vs. 67 y, female 56% vs. 64%, recurrent episode 4 vs. 3.1, CDI severity score 1.4 vs. 1.2. 95% (19/20) of patients who received cFMT via colonoscopy experienced sustained clinical cure vs. 85% (11/13) of patients who received capsule. One patient experienced an adverse event from capsule with nausea and vomiting, which resolved without sequelae. 2 of the 3 patients that experienced treatment failure received cFMT from the same donor Due to recurrent episodes. The cost of cFMT was $635 for capsules and $485 for solution which was far less than recurrent CDI associated cost.

Conclusion

cFMT is a viable alternative to traditional FMT and was both clinically and economically beneficial in patients with recurrent CDI in a community hospital. Further studies needed to confirm above findings.

Disclosures

All authors: No reported disclosures.
Cost Effectiveness Analysis of Fecal Transplant Delivery Methods for Recurrent Clostridium difficile Infections in Outpatients
Authors: Walker Jeremey , Gundacker Nathan , Rodriguez Martin , Eaton Ellen
Published: October 2017

Background

Clostridium difficile infection (CDI) accounts for more than $1 billion annually in US health care costs. Recurrent CDI (RCDI, recurrence within 8 weeks of initial treatment) contributes substantially to this cost. The objective of the study was to compare the cost effectiveness of FMT delivered via colonoscopy vs. blind nasogastric tube (NGT) in outpatients. We hypothesized that FMT by NGT would be cost-effective given its low risk and simplicity.

Methods

A decision-analytic simulation model compared the cost effectiveness of FMT by colonoscopy vs. NGT from a third-party payer perspective. Our base case cure rates were derived from a cohort receiving outpatient RCDI treatment at our institution. Cure was defined as resolution of symptoms for ≥ 90 days. Procedural cost and consultation was defined by average reimbursement to a large southeastern medical center in 2016 USD based on current procedural terminology (CPT) codes, and cost of disease states were derived from published literature. Health utilities were defined by quality of life year (QALY) based on published literature. Incremental Cost Effectiveness ratio (ICER) was defined as the cost per additional QALY gained. We assumed a 90 day time horizon. One-way sensitivity analysis was performed on all variables using ranges defined by published literature. We used TreeAge Software (Williamstown, MA).

Results

In the base case, FMT by colonoscopy was dominant (more effective and less costly) than NGT, with cost of $1,568/QALY vs. $1,910/QALY respectively. Cure rates of FMT by colonoscopy vs. NGT (100% vs. 87%) had the largest impact on ICER based on one-way sensitivity analysis. Therefore, a subsequent two-way sensitivity analysis was conducted to compare cure rates of both delivery methods and found that NGT delivery is cost effective as cure rates approach colonoscopy delivery cure rates within 5 percentage points.

Conclusion

Contrary to our hypothesis, our decision model supports FMT by colonoscopy as the preferred delivery method in outpatients with RCDI relative to NGT delivery. Additional costs of colonoscopy delivery are off-set by the improved cure rate leading to lower overall costs. As cure rates from NGT delivery are optimized, NGT may become the preferred method for FMT delivery.

Disclosures

All authors: No reported disclosures.
Ribotypes Matter, Significance of Clostridium difficile Ribotypes in Cancer Patients with Diarrhea
Authors: Guevara Eduardo Yepez , Yalamanchili Harika , Chao Andrew , Garey Kevin , Bhatti Micah , Aitken Samuel L , Okhuysen Pablo C
Published: October 2017

Background

Cancer patients are at increased risk for Clostridium difficile infection (CDI) due to frequent health care contact, chemotherapy, use of antibiotics, and immunosuppression. Distinct ribotypes are associated with CDI adverse outcomes. Ribotypes 14-020 are the predominant ribotypes in many hospitals. We examined the contribution of C. difficile ribotypes to CDI severity, response to therapy and outcomes in this population.

Methods

Demographic and clinical data were collected from 90 cancer patients with a first episode or first recurrence of CDI identified by two-step PCR followed by EIA for A/B toxins. Fluorescent PCR ribotyping (FPCR) was performed on fecal isolates. We identified 27 distinct ribotypes between October 2016 and January 2017. Clinical outcomes were studied in three FPCR subgroups. Group I (GI, n = 27) included F014-020, group II (GII, n = 17) included virulent types 002, 027, 078–126, 244 and group III (GIII, n = 46) included the rest. Treatment failure was defined as no response after at least 3 days of a CDI treatment regimen. CDI severity was determined using Zar’s criteria, presence of bacteremia and ICU stay.

Results

The proportion of patients >50 yrs. old, with health care onset CDI (31%), primary CDI (92.2%), and on active chemotherapy (70%) was similar across the three groups. At presentation, disease severity was similar in all groups; However, patients in GII were more likely to have detectable toxin A/B by EIA compared with GI and GIII (53% vs. 23%, P = 0.015) and higher treatment failure rates (56%) when compared with GI (15% P = 0.007) and GIII (16%, P = 0.004). Bacteremia was more common in GIII (28%) compared with GII (0%) P = 0.041 and GI 7% P = 0.007. Patients in GI experienced fewer complications when compared with those in GIII P = 0.025. No differences in sustained clinical response, recurrence, ICU stay or all cause 90-day mortality were found between the groups.

Conclusion

Cancer patients with CDI due to GII ribotypes are more likely to excrete fecal toxin A/B and fail conventional therapy. In contrast, patients in GI and GIII were more likely to respond to therapy. GI was associated with fewer complications. Of interest, GIII was associated with bacteremia. Evaluation of C. difficile ribotypes is clinically relevant in cancer patients with CDI.

Disclosures

All authors: No reported disclosures.
Successful Response to Microbiota-Based Drug RBX2660 in Patients with Recurrent Clostridium Difficile Infection is Associated with More Pronounced Alterations in Microbiome Profile
Authors: Khanna Sahil , Blount Ken , Jones Courtney , Shannon Bill , Carter Sharina
Published: October 2017

Background

Recurrent Clostridium difficile infections (rCDI) are associated with decreased diversity and altered intestinal microbiome compared with healthy patients. RBX2660, a standardized microbiota-based drug, is designed to restore microbiome diversity and composition in patients’. The effect of RBX2660 on rCDI patient microbiomes was evaluated by comparing pre- and post-treatment samples from PUNCH CD 2—a randomized, double-blind, placebo-controlled study.

Methods

rCDIsubjects were randomized to receive blinded treatments of 2 doses of RBX2660 (Group A), 2 doses of placebo (Group B), or 1 dose each of RBX2660 and placebo (Group C), by enema 7 days apart. Subjects submitted stool samples at baseline, day 7, 30, and 60 after treatment. Stool samples from responders to RBX2660 treatment per protocol defined as the absence of CDI for 8 weeks after treatment were compared with non-responders.

Relative taxonomic abundances at the class level were determined using 16s rRNA sequencing analysis for 94 stool samples from 45 patients in Groups A and C. Relative abundance data were grouped longitudinally using Bray-Curtis dissimilarity index. Analyses were performed based on the Dirichlet-Multinomial distribution to compare group mean relative taxonomic abundances; Simpson and Shannon diversity indices were compared among groups longitudinally.

Results

Baseline patient microbiomes were similar across response groups. RBX2660 treatment shifted the relative microbiome densities with taxa-specific increase in Bacteroidia, Clostridia, and decrease in Gamma-proteobacteria abundance. A larger shift from baseline microbiome was seen in responders to RBX2600 compared with non-responders (Figure 1). Microbiome changes in responders were durable to 60 days. RBX2660 treatment increased Shannon and Simpson diversity at 7 days post-treatment in responders but not in non-responders (P < 0.05).

Conclusion

RBX2660 treatment shifts patient intestinal microbiomes with greater alterations seen in those with a successful clinical outcome.

Funded by Rebiotix Inc., Roseville, MN.

Disclosures

S. Khanna, Rebiotix, Inc.: Scientific Advisor, Consulting fee; K. Blount, Rebiotix, Inc.: Employee, Salary; C. Jones, Rebiotix, Inc.: Employee, Salary; B. Shannon, Rebiotix, Inc.: Research Contractor, Consulting fee; S. Carter, Rebiotix, Inc.: Research Contractor, Consulting fee
Initial Oral Vancomycin vs. Oral Vancomycin After Metronidazole for Severe Clostridium difficile Infection
Authors: Shah Sunish , Ereshefsky Benjamin , Pontiggia Laura , Cawley Michael
Published: October 2017

Background

Treatment of severe Clostridium difficile infection (CDI) with oral vancomycin (oVAN) is known to be superior to treatment with metronidazole. However, previous studies have not evaluated the impact on patients when oVAN therapy is delayed after diagnosis or suspicion of severe CDI.

Methods

This was a single-center, retrospective study of adult patients who were diagnosed with severe CDI as defined by a white blood cell (WBC) count greater than 15,000 cells/mm3. The primary outcome was in-hospital mortality between patients treated initially with oVAN vs. delayed oVAN after metronidazole. Secondary outcomes included clinical cure by day 10, post-infection length of hospitalization, the time to resolution of leukocytosis and renal function at the end of treatment. Leukocytosis was defined as a WBC greater than 12,000 cells/mm3. Patients were excluded if they received oVAN for a previous episode of CDI, were receiving treatment for a concurrent infection, were receiving high-dose steroids, or received metronidazole or oVAN within 5 days preceding CDI diagnosis.

Results

A total of 121 patients were included. Overall, 49% of patients were female and the median age was 67 years old. 101 patients comprised the initial oVAN group, while 20 patients comprised the delayed oVAN group. Baseline demographics did not differ significantly between groups other than the time to initiation of oVAN (0.33 vs. 3.18 days, P < 0.001). There was no significant difference in in-hospital mortality for patients in the initial oVAN treatment group compared with those who had delayed oVAN therapy (5% vs. 15%, P = 0.13). Patients who received oVAN initially experienced a higher rate of clinical cure by day 10 (49.5% vs. 20%, P = 0.02), a shorter median post-infection length of hospitalization (7 days vs. 13 days, P < 0.001), a shorter median time to resolution of leukocytosis (3.9 days vs. 10.4 days, P = 0.01), and were less likely to have an end of treatment serum creatinine greater than 1.5 times their baseline (8.7% vs. 29.4%, P = 0.03).

Conclusion

Patients who receive oVAN as their initial treatment for severe CDI have improved clinical outcomes compared with those initially treated with metronidazole.

Disclosures

All authors: No reported disclosures.
Clostridium difficile Infection in Hematopoietic Stem Cell Transplant Patients: A Single-center Experience
Authors: Majeed Aneela , Larriva Marti , Iftikhar Ahmad , Mushtaq Adeela , Hassan Nida , Hamadani Auon A , Khalid Nageena , Lim Melissa , Zangeneh Tirdad , Anwer Faiz
Published: October 2017

Background

C. difficile infection (CDI) is the most common cause of nosocomial infections in U.S. and leading cause of gastroenteritis associated death. Incidence of CDI in hematopoietic stem cell transplant (HSCT) patients has been reported between 5.7% to 24.7% during first year after HSCT. Literature review reveals many risk factors i.e., allogenic-HSCT, extremes of age, myeloablative conditioning, prior vancomycin resistance (VRE) colonization, pre-transplant C. difficile colonization, severe mucositis, graft vs. host disease (GVHD), duration and type of antibiotics used, immunosuppression, proton pump inhibitor use and NAP1 C. difficile strain.

Methods

To study incidence and different variables for CDI, we performed a retrospective review of medical records of adult patients who underwent HSCT between 2013 and 2016 at our center. REDCap database was used to record key variables related to each patient’s HSCT and CDI, keeping in mind HIPPA guidelines. Categorical data were summed up as percentages and counts and numeric data as means, medians, standard deviations and ranges.

Results

A total of 181 HSCT recipients were included. Incidence of CDI was 10% (18 Patients). Cohort’s most common underlying malignancy was multiple myeloma (35.4%). 70% had autologous HSCT and 30% had allogenic HSCT. Among allogenic transplants, 53% had matched unrelated donor. Peripheral blood was the most common stem cell source (93%). Most common myeloablative conditioning regimen was melphalan (70%). 27% patients were on PPIs. 4% had PEG/NG tube placed and 12% were on TPN. 10% had diabetes mellitus. 5 patients had previous episodes of CDI. 69% developed mucositis. 5% patients developed acute GVHD. 6% had VRE colonization while 66% had no documentation for VRE. Out of positive CDI cases, 17% were NAP1 positive. No episode of ileus or mega colon was documented. Most common treatment regimen were metronidazole 500 mg per orally every 8 hourly (65%) and vancomycin 125 mg per orally four times a day (58.8%).

Conclusion

This single-center study demonstrates that CDI has 10% incidence in patients undergoing HSCT. Risk factors include neutropenia, high dose chemotherapy, mucosal damage and provision of broad spectrum antibiotic prophylaxis. Data on CDI prophylaxis in these patients is emerging and randomized prospective trials are needed.

Disclosures

All authors: No reported disclosures.
Impact of Clostridium difficile Infection on Patients’ Quality of Life: a French Hospital Prospective Study
Authors: Barbut Frederic , Galperine Tatiana , Vanhems Philippe , Le Monnier Alban , Jeanbat Viviane , Duburcq Anne , Alami Sarah , Bensoussan Caroline , Fagnani Francis
Published: October 2017

Background

Few data are available on the impact of episodes of Clostridium difficile infection (CDI) on quality of life. The Cdiff32, a new specific health-related quality of life questionnaire recently validated, allows such a measurement (Garey et al. J Clin Gastroenterol 2016 Sep;50(8):631–7).

Methods

An observational prospective study was performed in 7 French acute-care facilities in 2016. All consecutive patients presenting with a bacteriologically-confirmed CDI during a hospital stay, regardless of reason for hospitalization, were enrolled. Two instruments were presented to patients at 7(±2) days after CDI diagnosis: the Cdiff32 and a generic questionnaire the EQ-5D-3L. The Cdiff32 comprises 32 self-administered questions about the impact of CDI in 3 broad domains (physical, mental and social). The physical domain differentiates general (6 questions) and specific physical complaints (8 questions). The mental domain comprises 14 questions about current and future anxiety. Four questions cover the impact on social relationships. Each item is scored from 0 (worst score) to 100 (best score) and they are aggregated by domain and globally. Clinical variables were collected to characterize the infection severity (ZAR score) and comorbidities. A regression analysis of the Cdiff32 scores with the EQ-5D-3L was performed.

Results

80 patients were enrolled and 3 were excluded because of missing data. The median age was 71 years and 45% were males. The global Cdiff32 score was 50.4 (SD: 17.1) with a large variability among patients (min 18.3, max 90.2). The highest impact of CDI was observed on the general physical complaints (41.6), as well as the level of current anxiety (41.6). The score relating to the social relationships was the highest (63.7). The severity of CDI (as defined by the Zar score) and the global Cdiff32 score were correlated essentially through the physical sub-score (P = 0.0154). Patients with recurrences had a lower mental score compared with patients with an initial episode (P = 0.0582). The regression analysis of global Cdiff32 score and EQ-5D-3L utility score showed a positive relationship (R2=0.317).

Conclusion

The Cdiff32 allowed to estimate the important impact on quality of life of CDI especially on the physical domain.

Disclosures

All authors: No reported disclosures.
Clostridium difficile Testing Algorithm: Is There a Difference in Patients Who Test Positive by Enzyme Immunoassay vs. Those Who Only Test Positive by Nucleic Acid Amplification Methodology?
Authors: Polak Jonathan , Odili Ogheneruona , Craver Mary Ashleigh , Mayen Anthony , Purrman Kyle , Rahman Asem , Sang Charlie Joseph , Cook Paul P
Published: October 2017

Background

Testing for Clostridium difficile infection (CDI) commonly involves checking for the presence of toxins A and B by enzyme immunoassay (EIA) or nucleic acid amplification (NAA). The former is very specific, but not very sensitive. The latter is very sensitive. Beginning in 2011, our hospital incorporated an algorithm that involved testing liquid stool specimens for glutamate dehydrogenase (GDH) and toxin by EIA. For discrepant results, the stool specimen was tested for the presence of toxin by NAA. We sought to determine whether there was a difference in the baseline characteristics or outcomes between the two groups.

Methods

We performed a chart review of all subjects who tested positive for CDI by either method between 2011 and 2016 at Vidant Medical Center, a 909 bed, tertiary care teaching hospital. Testing was only performed on liquid stool specimens. Subjects less than 18 years of age were excluded. Repeat positive specimens were excluded. We collected demographic data including age, gender, baseline temperature, white blood cell count, and serum lactate and albumin. Length of stay and in-hospital mortality were also determined for both groups. Comparison of the two groups was done using t-test for continuous and chi-square analysis for categorical variables.

Results

Over the 6 year period, there were 535 positive test results. 243 specimens tested positive by EIA/GDH (EIA +); 292 specimens tested positive by GDH/NAA (NAA +). Compared with the EIA + group, the NAA + group was younger (61.8 years vs. 65.1 years, P = 0.01). There were no statistical differences in the presence of abdominal tenderness, temperature >38oC, serum albumin, serum lactate, length of stay, or mortality between the two groups. The EIA + group was statistically more likely to have leukocytosis (WBC >20,000 cells/mm3) at the time of the CDI testing compared with the NAA + group (P = 0.0002).

Conclusion

There do appear to be some clinical differences in the presentation of subjects who test positive for CDI by EIA/GDH compared with those who test positive only by GDH/NAA. These differences do not appear to affect length of stay or mortality.

Disclosures

P. P. Cook, Gilead: Grant Investigator, Grant recipient; Merck: Grant Investigator, Grant recipient; Pfizer: Grant Investigator and Shareholder, Grant recipient
Toxin Detection by Cell Culture Neutralization Assay [CYT] and Toxin based EIA [Tox EIA] among Recurrent Episodes of CDI Diagnosed by PCR
Authors: Kamboj Mini , Mcmillen Tracy , Chow Hoi Yan , Brite Jennifer , Babady N Esther
Published: October 2017

Background

The Ad Hoc C. difficile surveillance working group defines recurrent C. difficile infection as a second episode occurring >8 weeks after the index case. Due to its high sensitivity, diagnosis of recurrent CDI by PCR is extremely challenging in patients who may have persistent, PCR detectable shedding of toxigenic C. difficile (TCD) for an extended period of time after treatment of the initial CDI episode. CYT, which detects C. difficile toxin antigen, is a cumbersome test to perform but is considered as the current clinical diagnostic gold standard for CDI diagnosis. Aim: To determine the CYT and Toxin A/B EIA positivity among patients with recurrent CDI episodes detected by PCR. We further characterized the performance of diagnostic tests based on whether the recurrent episode was a relapse or reinfection.

Methods

During a three month study period, CYT and Tox A/B EIA was performed on consecutive stool samples submitted from PCR positive recurrent episodes of CDI. For the purpose of this study, recurrence was defined as a second episode of CDI that occurred within 120 days from the most recent episode. MLST analysis was performed as previously described to characterize relapse and reinfection among the recurrent episodes (2).

Results

Thirty-five recurrent episodes occurred over the study period. 21/35 [60%] were positive by CYT and 12/35 [34%] by Tox A/B EIA. Among the recurrent CDI episodes, 16 (46%) were genotypical confirmed as relapse with the original infecting strain. Majority of these relapses were positive by CYT (81%) when compared with Tox EIA (43%). Among patients with geno typically confirmed reinfection (n = 8), CYT and EIA positivity was 63 % and 50 % respectively. For the remaining 11 episodes, TCD was not retrievable in culture, CYT and EIA positivity among this group was 27 % and 9 % respectively.

Conclusion

Forty percent of recurrent CDI episodes detected by PCR could not be confirmed by CYT. EIA missed 66 % of CYT positive recurrent CDI. The performance of CYT and EIA varied among recurrences due to relapse and reinfection. These results have significant implication for reporting of CDI HAI rates.

Disclosures

All authors: No reported disclosures.
Clinical Correlation of a Clostridium difficile Testing Algorithm Reflexing PCR Positive Specimens to Toxin Enzyme Immunoassay (EIA)
Authors: Rios Maria Bueno , Karichu James , Deshpande Abhishek , Fraser Thomas , Isada Carlos , Richter Sandra S
Published: October 2017

Background

An algorithm promoted in the United Kingdom reflexes specimens positive for C. difficile by a nucleic acid amplification test (NAAT) to toxin EIA. Samples positive by NAAT and negative by toxin EIA are reported as “C. difficile could be present (ie, potential C. difficile excretor).” We explored the potential utility of this algorithm to distinguish C. difficile infection (CDI) from colonization compared with retrospective clinical assessment.

Methods

Liquid stool specimens (n = 300) from inpatients (or the Emergency Department) submitted to the Cleveland Clinic Microbiology laboratory for C. difficile PCR testing (Cepheid Xpert C. difficile/Epi) with positive results were included in the study. The CDIFF QUICK CHEK COMPLETE GDH/toxin EIA assay (Alere) was performed according to manufacturer’s instructions. The charts of all patients were reviewed by Infectious Diseases physicians blinded to the EIA results. Using the American College of Gastroenterology (ACG) classification system, CDI status was determined to be mild, moderate, severe, or complicated. Patients without significant diarrhea (<3 unformed stools / 24 hours) were considered colonized. Those without documentation of stools were classified as indeterminate. Correlation of clinical assessment with EIA results was assessed.

Results

Most of the PCR positive specimens (75%) were toxin EIA negative. Correlation of clinical assessment with toxin EIA is summarized in the table below. Among patients colonized vs. those with CDI, the percentages with negative toxin EIA results were 80% and 73%, respectively. GDH antigen results were negative for 25 specimens—17 were from patients considered to have CDI.

Conclusion

Toxin EIA performed on samples positive for C. difficile by PCR does not reliably identify patients considered to have CDI with ACG criteria applied. GDH as an initial screen would not have detected 6.8% of patients with CDI.

Disclosures

S. S. Richter, bioMerieux: Investigator, Research support; BD Diagnostics: Investigator, Research support; Roche: Investigator, Research support; BioFire: Investigator, Research support; OpGen: Investigator, Research support
Impact of a Multi-disciplinary C. difficile Action Team
Authors: Heil Emily , Sivasailam Bharathi , Park SoEun , Diaz Jose , Von Rosenvinge Erik , Claeys Kimberly , Hopkins Teri , Leekha Surbhi
Published: October 2017

Background

Clostridium difficile infection (CDI) is associated with increased length of hospital stay, morbidity, mortality, and cost of hospitalization. Early intervention by experts from multiple areas of practice such as gastroenterology (GI), infectious diseases (ID) and surgery can be essential to optimize care and increase utilization of novel treatment modalities such as fecal microbiota transplant (FMT) and minimally invasive, colon-preserving surgical management.

Methods

A multi-disciplinary C. difficile action team (MD-CAT) was implemented at University of Maryland Medical Center (UMMC) in March 2016 to engage appropriate specialty consultants in the care of CDI patients. The MD-CAT reviews positive C. difficile tests at UMMC and provides guidance and suggestions to the primary team including optimal antibiotic treatment (for CDI and any concomitant infection), and consultant involvement including ID, surgery, and GI, when appropriate. Using retrospective chart review, CDI patient management and outcomes were compared before and after implementation of the MD-CAT. Differences in the time to consults and frequency of interventional treatment was compared using Chi-square or Wilcoxon Rank-sum test.

Results

We compared 48 patients with CDI in the pre-intervention with 89 patients in the post-intervention period. Demographic and clinical characteristics of the groups were similar. MD-CAT intervention was associated with frequent (73%) modification or discontinuation of concomitant antibiotics. Median time to GI and ID consults was significantly shorter in the post group (P = 0.007 and P = 0.004, respectively). Five of 89 (5.6%) of patients received FMT or colon-preserving surgical intervention in the post-intervention group compared with no patients in the pre-intervention group. There was no difference in 30-day all-cause mortality or CDI recurrence between groups.

Conclusion

Early, multi-disciplinary action on patients with CDI increased the proportion of patients undergoing active specialty consultation and improved use of concomitant antibiotics. A larger sample size is needed to determine the effects of such a team on other clinical outcomes.

Disclosures

All authors: No reported disclosures.
The Impact of Diagnostic Stewardship on Clostridium difficile Infections
Authors: Bischoff Werner , Bubnov Andrey , Palavecino Elizabeth , Beardsley James , Williamson John , Johnson James , Luther Vera , Ohl Christopher , El Helou Guy , Huang Glen , Stehle John , Sanders John
Published: October 2017

Background

Clostridium difficile infections (CDI) pose a growing threat to hospitalized patients. This study assesses the impact of changing from a nucleic acid amplification test (NAAT) to a stepwise testing algorithm (STA) by using an enzyme immunoassay (GDH and toxin A/B) and confirmatory NAAT confirmation in specific cases.

Methods

In an 885 bed academic medical center a 24 month pre-/post design was used to assess the effect of the STA for the following parameters: rates of enterocolitis due to C.diff (CDE), NHSN C.diff LabID events, CDI complications, mortality, antimicrobial prescription patterns, cluster occurrences; and testing, treatment, and isolation costs. Inpatient data were extracted from ICD-9/10 diagnosis codes, infection prevention, and laboratory databases.

Results

The STA significantly decreased the number of CDE ICD9/10 codes, HO, CO, and CO-HCFA C.diff LabID event rates by 65%, 78%, 75%, and 75%, respectively. Similar reductions were noted for associated complications such as NHSN defined colon surgeries (-61%), megacolon (-64%), and acute kidney failure (-55%). CDE unrelated complication rates for colon surgeries and acute kidney failure remained constant while the diagnosis of megacolon decreased but not significantly (-71%; P > 0.05). Inpatient mortality did not change with or without CDE. Significant reductions were observed in the use of oral metronidazole (total: -32%; CDE specific: -70%) and vancomycin (total: -58%; CDE specific: -61%). There were no clusters detected pre-/post STA introduction. The need for isolation decreased from 748 to 181 patients post-intervention (-76%; P < 0.05). Annual cost savings were over $175,000 due to decreases in laboratory testing followed by isolation, and antibiotic use.

Conclusion

The switch to an STA from NAAT did not affect the diagnosis, treatment, or control of clinically relevant CDI in our institution. Benefits included avoidance of unnecessary antibiotic treatment, reduction in isolation, achieving publicly reported objectives, and costs savings. Selection of clinically relevant tests can help to improve hospitalization and treatment of patients and should be considered as part of diagnostic stewardship.

Disclosures

All authors: No reported disclosures.
Antibiotic Exposure and Risk of Community-associated Clostridium difficile infection (CA-CDI): A Self-Controlled Case Series Analysis
Authors: DiDiodato Giulio , Fruchter Lauren
Published: October 2017

Background

CA-CDI accounts for up to 50% of all CDIs. Case–control studies (CCS) have been used to estimate the odds ratio (OR) of CA-CDI associated with antibiotic exposure. These ORs demonstrate significant heterogeneity across studies. Unlike CCS, a self-controlled case series (SCCS) design can be used to control for all time-invariant confounders leading to less biased effect estimates.

Methods

Adults (≥18 years) registered (N = 139,670) with the Barrie and Community Family Health Team (BCFHT) were included in the study. Cases were defined as any patient with an incident case of CA-CDI and ≥1 antibiotic exposure occurring between January 1, 2011 and December 31, 2016. The SCCS model was used to estimate the association between antibiotic exposure and CA-CDI. The SCCS model yields estimates of the relative incidence rate of CA-CDI in exposure periods relative to non-exposure periods within a case. Exposure periods were defined as starting two days after any antibiotic prescription and ending 60 days later. Multiple exposure periods and time-varying confounders due to calendar year were included in the final model. The relative incidence rate ratio (IRR) was estimated using conditional poisson regression analysis. Proton pump inhibitor (PPI) use was included as an effect modifier. Antibiotics were divided into high-risk (fluoroquinolone, clindamycin, and cephalosporin) and low-risk exposures. Research ethics approval was obtained from the BFCHT research ethics board.

Results

Among 544 total CDI cases, N = 189 CA-CDI cases met the inclusion criteria. Any antibiotic exposure increases the risk by ≥2-fold, with no difference observed between high and low-risk groups (IRR=1.11, 95% CI 0.53–2.36) (Table 1).

Conclusion

Antibiotic exposure increases the risk of CA-CDI, with IRR estimates similar to those observed for healthcare-associated-CDI. This, along with the control of all time-invariant confounders by the SCCS method suggests a less biased effect estimate previously reported from CCS.

Disclosures

All authors: No reported disclosures.