bluuebunny/crossref_metadata_2025_split huggingface dataset:
In Vitro Activity of Lefamulin Against a Global Collection of Bacterial Pathogens Commonly Causing Community-Acquired Bacterial Pneumonia (CABP, SENTRY 2015)
Authors: Paukner Susanne , Sader Helio S , Streit Jennifer M , Flamm Robert K , Gelone Steven P 
Published: October 2017

Abstract

Background
CABP is the number one reason for death by infectious diseases worldwide and emerging resistance complicates its treatment. Lefamulin is the first semi-synthetic pleuromutilin antibiotic for IV and oral use in humans. It is currently in Phase 3 trials for the treatment of CABP in adults. Lefamulin effectively and selectively inhibits bacterial translation by binding to the peptidyl transferase center (PTC) via four H-bonds and other interactions at the A- and P-site resulting in an “induced fit.” This study investigated the activity of lefamulin and comparators against a contemporary set of bacterial pathogens associated with community-acquired respiratory infections collected worldwide.

Methods
Unique patients’ isolates (n = 2817) were collected globally in US (19.7%), Europe (36.9%), Latin America (5.7%) and Asia-Pacific region (37.6%) (30 countries, 116 sites) from adult and pediatric patients with respiratory tract infection (88.0%), bloodstream infections (5.5%) and other infections (2.4%). Lefamulin and comparators were tested by CLSI broth microdilution and susceptibility was determined using the CLSI (2017) breakpoints.

Results
LEF was the most potent compound tested, with 99.7% of all S. pneumoniae isolates being inhibited at a concentration of ≤0.25 mg/L (MIC50/90 values of 0.06/0.12 mg/L) and its activity was not affected by resistance to other antibiotic classes. S. pneumoniae isolates were largely susceptible to levofloxacin (99.1%) and ceftriaxone (96.5%), while 34.5%, 23.3% and 16.8% of isolates were resistant to macrolides, tetracycline and clindamycin, respectively. Lefamulin also showed potent activity against H. influenzae (MIC50/90 of 0.5/1 mg/L), including 22.0% of ß-lactamase producing strains, and M. catarrhalis (0.06/0.12 mg/L).

Conclusion
Lefamulin demonstrated potent in vitro activity against this global collection of contemporary respiratory pathogens and its activity was unchanged regardless of resistance phenotype to the other antibiotic classes including macrolides, ß-lactams, tetracyclines or fluoroquinolones. These data support the continued clinical development of lefamulin for the treatment of respiratory tract infections, including CABP.

Disclosures
S. Paukner, Nabriva Therapeutics: Employee and Shareholder, Salary; H. S. Sader, Nabriva Therapeutics: Research Contractor, Research grant; J. M. Streit, Nabriva Therapeutics: Research Contractor, Research grant; R. K. Flamm, Nabriva Therapeutics: Research Contractor, Research grant; S. P. Gelone, Nabriva Therapeutics: Employee and Shareholder, Salary
In Vitro Activity of Omadacycline and Comparator Compounds Against Gram-positive Isolates Collected in the USA During 2016 as Part of a Global Surveillance Program
Authors: Huband Michael D , Pfaller Michael a , Sader Helio S , Flamm Robert K 
Published: October 2017

Abstract

Background
Omadacycline (OMC) is a broad spectrum aminomethylcycline antibacterial in late stage clinical development (PO and IV formulations) for treatment of acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP). OMC has potent in vitro activity against gram-positive (GP) pathogens expressing common resistance mechanisms to penicillins, tetracyclines, fluoroquinolones and macrolides.

Methods
A total of 4,122 GP isolates were collected in 2016 from 30 USA medical centers and included 2,366 staphylococci, 1,252 streptococci and 504 enterococci. A single isolate/patient/infection episode was included. Identifications were confirmed by matrix-assisted laser desorption/ionization mass spectrometry and susceptibility (S) testing was performed using reference broth microdilution methods.

Results
OMC was equally active against methicillin-susceptible (55.1% MSSA) and -resistant (44.9% MRSA) Staphylococcus aureus (SA; MIC50/90, 0.12/0.25 µg/mL). All SA were S to daptomycin (DAP), linezolid (LZD) and vancomycin (VAN). In MRSA, S was lower for levofloxacin (LEV; 28.2%), clindamycin (CLI; 69.9%), and erythromycin (ERY; 10.9%). OMC (MIC50/90, 0.12/0.5 µg/mL) and tigecycline (TGC; MIC50/90, 0.06/12 µg/mL) were the most active agents against coagulase-negative staphylococci (CoNS) and methicillin-R CoNS. S. pneumoniae (including penicillin- [12.8% resistant], ceftriaxone- and ERY-resistant strains), viridans group streptococci (VGS) and β-hemolytic streptococci (including ERY and tetracycline resistant strains) were inhibited by low levels of OMC (MIC50/90 0.06/0.06–0.12 µg/mL) and TGC (MIC50/90 0.03–0.06/0.06–0.12 µg/mL). OMC was highly potent against enterococci (MIC50/90 0.12/0.25 µg/mL) including vancomycin-R isolates. Vancomycin resistance rates were 4.3% and 66.5% in E. faecalis and E. faecium, respectively.

Conclusion
OMC demonstrated potent activity against susceptible and resistant GP pathogens often associated with ABSSSI and CABP including staphylococci, S. pneumoniae, β-hemolytic streptococci, VGS and enterococci. These data support further omadacycline clinical studies, especially in infections where resistant GP isolates occur.

Disclosures
M. D. Huband, Paratek Pharma, LLC: Research Contractor, Research grant; M. A. Pfaller, Paratek Pharma, LLC: Research Contractor, Research grant; H. S. Sader, Paratek Pharma, LLC: Research Contractor, Research grant R. K. Flamm, Paratek Pharma, LLC: Research Contractor, Research grant
Ceftazidime-avibactam and Meropenem Double Disk Diffusion Test for Identifying Carbapanem-Resistant Enterobacteriaceae and Distinguishing Between Serine and Metallo-β-Lactamase Producing Organisms
Authors: Lin Lynn-Yao , Critchley Ian , Melnick David 
Published: October 2017

Abstract

Background
Early detection of carbapenem-resistant Enterobacteriaceae(CRE) is crucial for selection of effective treatment. While KPC is the most prevalent carbapenemase in the US, phenotypic screening methods, such as the carbapenemase inactivation method (CIM) and CarbaNP, cannot easily distinguish between serine and metallo-β-lactamases (MBL). The aim of this study was to evaluate a simple double disk diffusion (DD) test to confirm carbapenem (meropenem) resistance (MER disk) and that resistance was due to a serine carbapenemase as indicated by susceptibility to ceftazidime-avibactam (CAZ-AVI disk). MBL-producing organisms are likely to be resistant to both MER and CAZ-AVI.

Methods
In total, 83 clinical isolates of Enterobacteriaceae were selected for the validation: 54 Klebsiella pneumoniae (KP), 16 Enterobacter cloacae (ECL) and 13 Escherichia coli (EC). All isolates were screened for specific β-lactamase genes (Checkpoints, Wageningen, Netherlands) and included KPC, OXA, IMP, VIM, NDM as well as strains with KPC and alterations on OmpK35 and OmpK36. Isolates were tested for susceptibility to MER and CAZ-AVI by disk diffusion and broth microdilution (BMD) per CLSI guidelines. Results were analyzed to evaluate suitability of the DD test to distinguish between serine and MBL-producing organisms.

Results
Overall correlation between disk and BMD was 97–100% for CAZ-AVI and 94–100% for MER. Among the 50 CRE that were susceptible to CAZ-AVI were strains positive for KPC, or OXA, or in combination with ESBLs. Among the 16 isolates that were resistant to both CAZ-AVI and MER were strains that produced MBLs such as IMP, VIM and NDM and included strains with alteration in OmpK35 and OmpK36. Among the 17 carbapenem-susceptible control strains all were susceptible to both agents and were positive for AmpC or ESBLs.

Conclusion
The CAZ-AVI and MER DD test was successful in confirming CRE phenotype and in distinguishing between serine carbapenemase-producing and MBL-producing organisms. The test will be useful in screening patients in future trials to evaluate the efficacy of CAZ-AVI in global CRE studies where MBL’s are more prevalent in other geographic regions. Both disks are commercially available and can be performed in most clinical laboratories.

Disclosures
L. Y. Lin, Allergan plc: Employee, Salary; I. Critchley, Allergan plc: Employee, Salary; D. Melnick, Allergan plc: Employee, Salary
Antimicrobial Activity of Dalbavancin Tested against Staphylococcus aureus with Decreased Susceptibility to Glycopeptides, Daptomycin, and/or Linezolid from United States (US) Medical Centers
Authors: Sader Helio S , Mendes Rodrigo E , Duncan Leonard R , Pfaller Michael A , Flamm Robert K 
Published: October 2017

Abstract

Background
Dalbavancin (DALBA) was approved by the US Food and Drug Administration (2014) and European Medicines Agency (2015) for treating acute bacterial skin and skin structure infections. Dalbavancin activity was assessed against a large collection of S. aureus clinical isolates with decreased susceptibility (S) to key antimicrobial agents used to treat severe S. aureus infections.

Methods
The organism collection included isolates with decreased S to vancomycin (VAN; MIC ≥2 μg/mL; n = 1,141), daptomycin (DAPTO; MIC ≥2 μg/mL [resistant (R) per CLSI and EUCAST]; n = 48), telavancin (TLV; MIC ≥0.12 μg/mL; n = 73), teicoplanin (TEICO; MIC ≥4 μg/mL [non-S (NS) per EUCAST]; n = 143), and/or linezolid (LNZ; MIC ≥8 μg/mL [R per CLSI and EUCAST]; n = 25). Isolates were selected among 59,903 US isolates tested in 2002–2016. S testing was performed by CLSI methods and MIC results were interpreted per CLSI and EUCAST criteria.

Results
Only 8 of 59,903 (0.01%) S. aureus isolates tested were categorized as DALBA-NS (MIC, &gt;0.25 μg/mL). DALBA retained activity against 99.3% of isolates with VAN MICs of ≥2 μg/mL (Table), whereas DAPTO (MIC50/90, 0.5/1 μg/mL) and LNZ (MIC50/90, 1/2 μg/mL) were active against 96.8% and 99.6% of isolates, respectively. DALBA (Table) and VAN (MIC50/90, 2/2 μg/mL) retained activity against 95.8% of DAPTO-NS S. aureus. When tested against TEICO-NS (EUCAST) isolates, S rates for DALBA, DAPTO, VAN, and LNZ were 95.1%, 95.8%, 97.9%, and 100.0%, respectively; and DALBA was 4- to 32-fold more potent than these comparator agents. All LNZ-R isolates (100.0%) were S to DALBA (MIC50/90, 0.06/0.06 μg/mL), DAPTO (MIC50/90, 0.5/0.5 μg/mL), and VAN (MIC50/90, 1/2 μg/mL), but DALBA was 8- and 16- to 32-fold more potent than DAPTO and VAN, respectively. MRSA rates ranged from 71.2–96.0% among these R subsets.

Conclusion
DALBA retained potent in vitro activity against S. aureus isolates, displaying decreased susceptibility to agents commonly used to treat serious infections and was consistently more potent than comparator agents.

Disclosures
H. S. Sader, Allergan: Research Contractor, Research grant; R. E. Mendes, Allergan: Research Contractor, Research grant; L. R. Duncan, Allergan: Research Contractor, Research grant; M. A. Pfaller, Allergan: Research Contractor, Research grant; R. K. Flamm, Allergan: Research Contractor, Research grant
In vitro Activity of Ceftaroline Against Pathogens Collected Globally from the AWARE Surveillance Program, 2016
Authors: Hackel Meredith , Iaconis Joseph , Sahm Dan 
Published: October 2017

Abstract

Background
Ceftaroline, the active metabolite of ceftaroline fosamil, is a cephalosporin developed for treating infections caused by Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA), Streptococcus pneumoniae, β-hemolytic streptococci, and some Gram-negative pathogens. This study reports the in vitro activity of ceftaroline against clinically relevant isolates collected in 2016 from the AWARE Surveillance Program.

Methods
22,752 non-duplicate methicillin-sensitive S. aureus (MSSA), MRSA, S. pneumoniae, β-hemolytic streptococci (S. pyogenes, S. agalactiae, S. dysgalactiae) Haemophilus influenzae, and extended spectrum β-lactamase (ESBL)-negative Enterobacteriaceae were collected from (n/%) Asia/South Pacific (4,215/18.5%), Europe (12,962/57.0%), Latin America (3,384/14.9%), and Middle East/Africa (2,191/9.6%) during 2016. Isolates were from (n/%) complicated intraabdominal (2,149/9.5%), complicated urinary tract (3,029/13.3%), complicated skin and skin structure (8,271/36.4%), blood stream (2,422/10.6%) and lower respiratory tract infections (6,881/30.2%). MIC values were determined by broth microdilution and interpreted using CLSI breakpoints.

Results
Ceftaroline activity, based on % susceptibility (%S) and MIC90, is shown in the table. Ceftaroline was active in vitro against both Gram-positive (100% of MSSA, 93.6% of MRSA and 99.7% of S. pneumoniae) and Gram-negative (99.7% of H. influenzae and 91.7% of ESBL-negative Enterobacteriaceae) isolates.

Conclusion
Based on these data generated with isolates collected in 2016, ceftaroline exhibited potent in vitro activity against clinically relevant isolates, with &gt;91% of all isolates susceptible at their CLSI breakpoints.
Funding: This study was sponsored by AstraZeneca. The AstraZeneca product ceftaroline fosamil was acquired by Pfizer in December 2016.

Disclosures
J. Iaconis, AstraZeneca: Employee and Shareholder, Salary and Shareholder in AstraZeneca
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

Abstract

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 &gt;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

Abstract

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 &gt;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

Abstract

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

Abstract

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.