bluuebunny/crossref_metadata_2025_split huggingface dataset:
In Vitro Activity of Lefamulin against S. aureus Collected Worldwide from Hospitalized Patients with Bacterial Pneumonia
Authors: Paukner Susanne , Flamm Robert K , Schuchert Jason , Gelone Steven P , Sader Helio S 
Published: October 2017

Abstract

Background
S. aureus (SA) is a well-recognized cause of pneumonia from both the community and hospital settings. The clinical management of SA pneumonia is complicated by the invasive infection it can cause and the high prevalence of methicillin-resistance (MR). Lefamulin (LEF) is the first semi-synthetic pleuromutilin antibiotic for IV and oral use in humans. LEF is the first semi-synthetic pleuromutilin antibiotic for IV and oral use in humans and it specifically inhibits bacterial protein synthesis. LEF is currently in Phase 3 trials for the treatment of community-acquired bacterial pneumonia (CABP). This study investigated the in vitro activity of LEF and comparators against SA strains collected from patients hospitalized with pneumonia in 2015.

Methods
1273 unique SA isolates were collected from hospitalized patients with pneumonia worldwide in 28 countries (33 sites) in 2015 as part of the SENTRY surveillance program. Isolates included 401 hospital-acquired (HA) SA (259 from ICU, 152 from ventilator associated pneumonia, VAP). Susceptibility testing was conducted using the CLSI broth microdilution method and susceptibility was interpreted per CLSI 2017 breakpoint criteria.

Results
LEF was the most potent compound tested, with 99.7% of all SA isolates being inhibited at a concentration of ≤0.25 mg/L (MIC50/90 values of 0.06/0.12 mg/L) and irrespective of the collection source (ICU/non-ICU, VAP/non-VAP). 31.6% of isolates (n = 402) were MRSA of which 99.3% were inhibited at a LEF concentration of ≤0.25 µg/mL (MIC50/90, 0.06/0.12 mg/L). Susceptibility rates for all SA isolates were &gt;90% for ceftaroline, vancomycin, linezolid and doxycycline. Susceptibility to azithromycin, levofloxacin and clindamycin was limited, particularly among MRSA (see Table).

Conclusion
SA strains collected from patients hospitalized with pneumonia including HAP and VAP were highly susceptible to LEF regardless of the resistance phenotype to the other antibiotics tested. Due to its potent activity against resistant SA and the most prevalent typical and atypical respiratory pathogens, as well as the availability of IV and oral formulations, LEF has the potential to play a role in the empiric treatment of CABP and supports evaluation in HAP and VAP caused by SA.

Disclosures
S. Paukner, Nabriva Therapeutics: Employee and Shareholder, Salary; R. K. Flamm, Nabriva Therapeutics: Research Contractor, Research grant; J. Schuchert, Nabriva Therapeutics: Research Contractor, Research grant; S. P. Gelone, Nabriva Therapeutics: Employee and Shareholder, Salary; H. S. Sader, The Medicines Company: Research Contractor, Research grant
In vitro Activity of Fosfomycin, Alone and Combined with Cefepime and Meropenem, Against Carbapenemase-Producing Gram-Negative Bacteria
Authors: Wiederhold Nathan P , Jorgensen James H , McElmeel Maria , Najvar Laura K , Catano Gabriel , Patterson Thomas F 
Published: October 2017

Abstract

Background
Multi-drug resistant (MDR) gram-negative bacteria are serious clinical threats. Fosfomycin (FOF) is an epoxide antibiotic that causes bacterial cell death via disruption of cell wall synthesis. The addition of fosfomycin has been shown to restore susceptibility to other agents against MDR P. aeruginosa. We evaluated the in vitro activity of the new IV fosfomycin formulation, alone and combined with cefepime (FEP) and meropenem (MEM), against carbapenemase-producing Enterobacteriaceae.

Methods
80 carbapenemase-producing isolates, including 31 metallo β-lactamase producing isolates (29 NDMs and 1 each IMP and VIM), 48 KPCs, and 1 OXA-48, were used. The in vitro susceptibility of FOF, FEP and MEM were tested by agar dilution with glucose-6 phosphate by CLSI methods. Combination testing was then performed against 25 representative isolates using fixed concentrations of FOF (8, 16, 32, and 64 mg/mL) at 0.25X the MIC of FOF alone with doubling dilutions of FEP and MEM.

Results
Reduced activity was observed for FEP and MEM against the carbapenemase-producing isolates (Table). 36.2% of the isolates were NDM1 and 60% were KPCs. A total of 92.5% of the isolates were resistant to either FEP or MEM. FOF plus MEM resulted in synergistic activity (4-fold reduction in MEM MIC at 0.25X FOF MIC) against 12 of 25 isolates used for combination testing, with no antagonism observed. For these 12 isolates, MEM MICs ranged from 2 to 16 mg/mL when combined with FOF vs. 16 to 128 mg/mL when tested alone. When combined with FEP, synergistic activity was also observed against 6 of the 25 isolates. However, antagonism was observed against 3 isolates with this combination.

Conclusion
The combination of FOF plus MEM resulted in synergistic activity against approximately half of the KPCs and metallo β-lactamase producing bacteria. Synergistic activity was observed less often with FOF plus FEP, although antagonism was uncommon. Further studies are warranted to determine the in vivo efficacy of FOF combinations. Table: MICs Alone

Disclosures
All authors: No reported disclosures.
Activity of Ceftolozane-Tazobactam (C/T) against Escherichia coli Isolates from U.S. Veterans in Relation to Co-resistance and Sequence Type 131 (ST131) H30/H30Rx Status
Authors: Johnston Brian D , Thuras Paul , Johnson James R 
Published: October 2017

Abstract

Background
E. coli ST131, with its resistance-associated H30 and H30Rx clonal subsets, causes most antimicrobial-resistant E. coli infections, especially among veterans. The activity of the novel combination agent C/T against ST131 is undefined.

Methods
E. coli clinical isolates (n = 595), including (per VAMC) 10 each ciprofloxacin-resistant and susceptible isolates, plus archived ESBL isolates, were collected from 24 VAMCs across the U.S. (2011). ST131, H30, and H30Rx were detected by clonal PCR. Microdilution MICs were determined for C/T and 5 comparators (piperacillin-tazobactam [TZP], levofloxacin [LVX], gentamicin [GEN], ceftazidime [CAZ], and meropenem [MEM]). Categorical resistance and MICs were compared statistically with resistance category and H30/H30Rx status.

Results
Total resistance prevalence was &lt; 5% for C/T (3.5%) and MEM (0%), vs. from 7.9% (TZP) to 59% (LVX) for other comparators (Table 1). Resistance prevalence generally increased by resistance category from FQ-S through FQ-R to ESBL, and by clonal subgroup from non-H30 through H30 to H30Rx.

Conclusion
C/T is broadly active against E. coli clinical isolates from veterans, notwithstanding significant variation by resistance category and ST131-H30/H30Rx status; it outperformed all non-carbapenem comparators. C/T should prove useful as a carbapenem-sparing agent against multidrug-resistant E. coli ST131 infections.

Disclosures
B. D. Johnston, Merck Sharpe & Dohme, Corp.: Collaborator, Research support Actavis: Collaborator, Research support; J. R. Johnson, Merck: Grant Investigator, Research grant Grant Investigator, Research grant
Activity of Meropenem-Vaborbactam Against Enterobacteriaceae Isolates Carrying blaKPC Collected Worldwide
Authors: Castanheira Mariana , Mendes Rodrigo E , Duncan Leonard R , Woosley Leah N , Flamm Robert K 
Published: October 2017

Abstract

Background
Meropenem-vaborbactam (MER-VAB) is a carbapenem-β-lactamase inhibitor combination with enhanced activity against KPC-producing Enterobacteriaceae recently evaluated in a phase 3 clinical trials for cUTIs and infections due to CRE. We analyzed the activity of MER-VAB against 517 isolates carrying blaKPC collected worldwide during 2014–16.

Methods
Enterobacteriaceae isolates (n = 34,069) from 34 countries were susceptibility (S) tested by reference broth microdilution method for MER-VAB (at fixed 8 µg/mL) and comparators. Carbapenem-resistant Enterobacteriaceae (CRE; CLSI criteria) were submitted to PCR/Sanger sequencing or next-generation sequencing for blaKPC screening.

Results
A total of 517 (1.5%) carried blaKPC and 6 variants were observed: 293 blaKPC-3, 218 blaKPC-2, 2 blaKPC-4, 2 blaKPC-17, and 1 each of blaKPC-2-like and blaKPC-12. Isolates were mainly K. pneumoniae (437), but also 32 E. cloacae, 13 K. oxytoca, 12 E. coli, 12 S. marcescens, and 4 other species. Isolates carrying blaKPC were detected in 17 countries. The occurrence ranged from &lt;0.1% to 11.3%, being higher in Brazil, Italy (9.3%), Poland (5.6%), and Argentina (5.2%). MER-VAB inhibited 514/517 (99.4%) isolates carrying blaKPC at ≤8 µg/mL and this compound was the most active agent tested against these isolates (MIC50/90, 0.12/1 µg/mL). Three isolates displaying elevated MER-VAB MIC values (&gt;8 µg/mL) co-harbored blaNDM-1 or blaOXA-48-like in addition to blaKPC or had a missense mutation on OmpK35. MER alone (MIC50/90, 32/&gt;32 µg/mL), imipenem (MIC50/90, &gt;8/&gt;8 µg/mL), and doripenem (MIC50/90, &gt;4/&gt;4 µg/mL) were not active against isolates harboring blaKPC. Amikacin (MIC50/90, 16/&gt;32 µg/mL) and gentamicin (MIC50/90, 2/&gt;8) µg/mL inhibited only 54.9% and 57.3% of the isolates (CLSI breakpoint). Colistin (MIC50/90, ≤0.5/&gt;8 µg/mL; 70.4% S/EUCAST breakpoint) and tigecycline (MIC50/90, 0.5/1 µg/mL; 99.4% S/US FDA criteria) were the most active comparators.

Conclusion
The occurrence of blaKPC is still low overall, but can be as high as 5–10% in a few countries and occur in species other than Klebsiella. KPC-producers are highly resistant to available antimicrobial agents and MER-VAB will be a useful alternative to treat infections caused by these organisms.

Disclosures
M. Castanheira, Rempex, a wholly owned subsidiary of The Medicines Company: Research Contractor, Research grant; R. E. Mendes, Rempex, a wholly owned subsidiary of The Medicines Company: Research Contractor, Research grant; L. R. Duncan, Rempex, a wholly owned subsidiary of The Medicines Company: Research Contractor, Research grant; L. N. Woosley, Rempex, a wholly owned subsidiary of The Medicines Company: Research Contractor, Research grant; R. K. Flamm, Rempex, a wholly owned subsidiary of The Medicines Company: Research Contractor, Research grant
Change in Bacterial Diversity of Fecal Microbiota Drives Mortality in a Hamster Model of Antibiotic-induced Clostridium difficile Colitis
Authors: Burdet Charles , Nguyen Thu Thuy , Saint-Lu Nathalie , Sayah-Jeanne Sakina , Hugon Perrine , Sablier-Gallis Frédérique , Ferreira Stéphanie , Andremont Antoine , Mentré France , Gunzburg Jean De 
Published: October 2017

Abstract

Background
C. difficile (C diff) infection results from antibiotic-induced changes in colonic microbiota. DAV131A, an oral adsorbent-based product, can sequester antibiotic (AB) residues in the gut and reduce mortality in a hamster model of moxifloxacin (MXF) or clindamycin (CM) induced C diffcolitis. We studied the link between changes of the bacterial diversity within the fecal microbiota and mortality in this model.

Methods
Male Syrian hamsters were administered 30 mg/kg MXF or 5 mg/kg CM subcutaneously once a day for 5 days (D1 to D5) and orally infected at D3 with 104C diffspores. They were orally administered various doses of DAV131A (0, and 200 to 900 mg/kg twice a day), from D1 to D8. Survival was monitored up to D16 and feces were collected (D1 and D3) to characterize the microbiota by 16S rRNA gene profiling. Changes of various α- (Shannon, Observed OTUs and Chao1) and β- (Bray-Curtis dissimilarity and [un]weighted UniFrac) diversity indices between D1 and D3 were obtained for each animal. We analyzed links between (i) DAV131A dose and changes of bacterial diversity and (ii) changes of bacterial diversity and mortality using non parametric tests and logistic regression.

Results
Data from 70 and 60 animals were available in the MXF and CM studies, among which 10 and 28 died, respectively. Increasing doses of DAV131A reduced mortality from 100% to 0% and reduced changes in bacterial diversity of the fecal microbiota. Very strong predictors of mortality were changes in Shannon and unweighted UniFrac indices, which were markedly less affected in hamsters who survived (see table below median (min; max) according to vital status and area under the ROC curve, AUROC).

Conclusion
The extent of AB-induced changes in gut bacterial diversity correlated with increased mortality in a hamster model of C diff colitis. Higher doses of DAV131A protected fecal microbiota disruption and hence mortality.

Disclosures
C. Burdet, Da Volterra: Consultant and Research Contractor, Consulting fee; N. Saint-Lu, Da Volterra: Employee, Salary; S. Sayah-Jeanne, Da Volterra: Employee, Salary; P. Hugon, Da Volterra: Employee, Salary; F. Sablier-Gallis, Da Volterra: Employee, Salary; S. Ferreira, Genoscreen: Employee, Salary; A. Andremont, Da Volterra: Consultant, Consulting fee; F. Mentré, Da Volterra: Consultant and Research Contractor, Consulting fee; J. De Gunzburg, Da Volterra: Consultant and Shareholder, Consulting fee
Factors Affecting Effectiveness of Fecal Microbiota Transplant
Authors: Mosby Danielle , Mcgraw Patty , Duffalo Chad , Drees Marci , Depalma Fedele , Herdman Christine , Myerson Scott , Bacon Alfred E 
Published: October 2017

Abstract

Background
Fecal microbiota transplant (FMT) is an effective treatment for relapsing Clostridium difficile infection (CDI). With more widespread use of this intervention, variable cure rates (70–95%) have been observed. We conducted this study to identify specific patient- and procedure-level factors affecting FMT effectiveness, hypothesizing that those patients with higher comorbidity, inadequate bowel preparation, and shorter retention of transplant would fail more frequently.

Methods
At our 2-hospital, &gt;1100-bed community-based academic center, we prospectively followed patients pre/post-FMT between June 2014-April 2017. To undergo FMT, patients must have ≥2 CDI relapses and failed vancomycin taper. We entered all FMT patients into a registry and followed them regularly for up to 1 year, collecting age, Charlson Comorbidity Index, number of CDI relapses, Boston bowel prep score, and stool retention time. FMT donor stool was obtained from OpenBiome (Boston, MA). We defined failure as recurrent CDI requiring treatment ≤8 weeks after FMT. We used 1-sided t-tests to test our hypotheses.

Results
During the study period, 41 patients (mean age 65 years, SD 17.6) underwent FMT. Most (37, 90%) were performed via colonoscopy, 1 via upper endoscopy, and 3 via oral preparation (capsules). FMT failure occurred in 10 patients (24.4%). Nearly half (n = 20) reported adverse events, including constipation, gas, abdominal pain, blood in stool, and fatigue. Three patients expired from comorbid disease, and 3 were lost to follow-up. Patients with higher Charlson scores failed more frequently (P = 0.04), and history of tumor (P = 0.03) and pulmonary disease (P = 0.04) were both associated with failure. No other factors, including age, retention time, and Boston bowel prep score, were associated with failure.

Conclusion
This study found that patients with multiple comorbid conditions, as defined by the Charlson index, are at risk for FMT failure. However, quality of bowel prep and retention time did not predict FMT failure. Future studies should include larger samples of FMT patients to determine whether specific comorbidities such as history of tumor and pulmonary disease are clinically significant predictors of FMT failure.

Disclosures
All authors: No reported disclosures.
Changes to the Composition of the Gastrointestinal Microbiome after Probiotics for Clostridium difficile Infection in Adults
Authors: Eggers Shoshannah , De Wolfe Travis , Barker Anna , Duster Megan , Dill-McFarland Kimberly , Suen Garret , Safdar Nasia 
Published: October 2017

Abstract

Background
Clostridium difficile infections (CDI) in the US have markedly increased. Disturbances to the gastrointestinal (GI) microbiome due to antibiotic use predisposes patients to CDI. Probiotics are recommended to prevent GI microbiota changes during CDI antibiotic treatment, but efficacy is unknown. We conducted a randomized, double-blinded, placebo-controlled, examination of clinical and GI microbiota changes in subjects administered probiotics during a primary episode of CDI.

Methods
33 subjects with a primary episode of CDI were randomized to once daily oral probiotic, consisting of four different bacterial strains, or placebo for 4-weeks (week 0–4) concurrent to antibiotic treatment. Subjects completed a daily stool diary, and stool samples were collected at enrollment (week 0), at the end of the probiotic or placebo adjunct regimen (week 4), and 4 weeks post-treatment (week 8). DNA was extracted for 16S rRNA sequencing with Illumina MiSeq. Microbial diversity, richness, and community structure were compared using analysis of variance and permutational analysis of variance. Similarity percentage analysis identified the operational taxonomic units driving the variation in β diversity.

Results
The duration of diarrhea (P = 0.039) and total days of diarrhea (P = 0.005) both decreased in the probiotic group compared with the placebo group. Analysis of community structure showed significant differences between treatment groups overall (P = 0.017) and in both groups over time (P = 0.007), but not between groups at each individual time point. Subjects in the probiotic group had a higher abundance of the family Lachnospiraceae at week 4 than subjects in the placebo group. By week 8 the abundance of Lachnospiraceae did not differ between subjects administered probiotic or placebo.

Conclusion
Lack of difference in overall community structure between groups at each time point is likely due to concurrent antibiotic therapy. The differential abundance of Lachnospiraceae likely contributes to the differences in the diarrheal outcomes observed between groups, as it has previously been associated with attenuated C. difficile pathology. Shortening the duration of diarrhea from an initial CDI may reduce the spread of C. difficile and improve clinical outcomes.

Disclosures
All authors: No reported disclosures.
Incidence of Pediatric Community Associated Clostridium Difficile Infection Following Common Antibotics
Authors: Katz Margot Miranda , Parmar Deepika , Dang Rebecca , Alabaster Amy , Greenhow Tara 
Published: October 2017

Abstract

Background
As rates of pediatric community-associated (CA) Clostridium difficile infection (CDI) increase, additional research is needed to address rates of infection following common antibiotics.

Methods
This study was a retrospective review of the electronic health records of all children with stool specimens sent for C difficile from January first 2012 – December 31st2016 at Kaiser Permanente Northern California. Children with clinical symptoms consistent with CDI, confirmatory laboratory testing, no other identified causes of diarrhea, and community associated disease were defined as cases. Using outpatient and ED antibiotic prescription records for children, incidence rates were calculated for subsequent CA CDI for the most commonly prescribed antibiotics.

Results
Of 507 primary CDI cases in our cohort, 327 had any antibiotic use 2012–2015. There were 205 primary CDI cases that were preceded by an antibiotic in the previous 1–365 days. Many of these patients had more than 1 antibiotic in the preceding year.
Of those, rates of CA CDI were uncommon following common antibiotics. (Table) The highest rate of CA CDI followed ceftriaxone, cefdinir, ciprofloxacin and augmentin. The lowest rates were seen following penicillin, doxycycline and azithromycin. Ninety-three percent of the antibiotic prescriptions were in outpatients, 7% in inpatients.

Conclusion
As rates of CA CDI increase, clinicians should be aware of rates of infection following administration of common antibiotics. The most common antibiotics to cause CA CDI were third-generation cephalosporins (ceftriaxone and cefdinir) and ciprofloxacin.

Disclosures
All authors: No reported disclosures.
PCR Cycle-Threshold-Derived Toxin Identifies Patients at Low-Risk for Complications of C. difficile Infection Who Do Not Require Treatment
Authors: Hitchcock Matthew , Holubar Marisa , Tompkins Lucy , Banaei Niaz 
Published: October 2017

Abstract

Background
Literature suggests that toxin detection differentiates those who require treatment for C. difficile infection (CDI) from those who do not. In-house studies have shown that free toxin can be predicted with high negative predictive value at a predefined cycle threshold (CT) using Xpert tcdB PCR (Cepheid, Sunnyvale, CA). In October 2016, CT-toxin was added to the PCR result and a comment recommends against CDI therapy if CT-toxin is negative (CTtox-). Here we evaluate the effect of this reporting on treatment rates and outcomes of CTtox- patients.

Methods
Patients tested from October 2016 to Apr. 2017 with a positive Xpert PCR and CTtox- result were included. Clinical data were collected by retrospective chart review and analyzed with the Chi squared and Student t-tests using SPSS. Due to multiple comparisons, α=0.01.

Results
Of 1516 Xpert PCR tests, 248 (16.4%) were positive and 98 (39.5%) were CTtox-. Of these, 54 (55.7%) were treated. Patient characteristics and data at testing are shown below. There were no cases of CDI-related septic shock or toxic megacolon on review. Time to diarrhea resolution was significantly shorter in untreated patients and there was no difference in crude mortality or later onset of CTtox+ CDI.

Conclusion
This study demonstrates the impact of stand-alone PCR assay with toxin prediction on reducing CDI therapy rates and provides further evidence that PCR+/toxin- patients are at low risk for CDI-related complications and do not require treatment, though more data is needed in transplant populations.

Disclosures
N. Banaei, Cepheid: Collaborator, Research Contractor and Scientific Advisor, honorarium for advisory role and Research support