bluuebunny/crossref_metadata_2025_split huggingface dataset:
1353. In Vitro Activity of Lefamulin (LEF) Against Bacterial Pathogens Commonly Causing Community-Acquired Bacterial Pneumonia (CABP): 2016 SENTRY Data From the United States
Authors: Paukner Susanne , Flamm Robert K , Gelone Steven P , Sader Helio S 
Published: November 2018

Abstract

Background
LEF, the first pleuromutilin antibiotic for IV and oral use in humans, is in Phase 3 clinical trials for the treatment of CABP in adults. In the first of these to be completed, LEF demonstrated noninferiority to moxifloxacin ± linezolid. LEF inhibits bacterial translation by binding the 50S ribosomal subunit at the A- and P-sites in the peptidyl transferase center. CABP is a leading cause of infectious diseases in the United States and increasing antibacterial resistance complicates its treatment. This study investigated the in vitro activity of LEF and comparators against a contemporary set of bacterial respiratory pathogens collected in the United States.

Methods
Isolates (n = 1674, 1/patient) were collected from 32 medical centers in the United States as part of the SENTRY Surveillance Program. LEF and comparators were tested by CLSI broth microdilution methods, and susceptibility was determined using the CLSI (2018) breakpoints.

Results
LEF was the most active compound against Streptococcus pneumoniae (MIC50/90 of 0.12/0.12 µg/mL), and its activity was not affected by resistance to other antibiotic classes. S. pneumoniae isolates were susceptible to levofloxacin (99.1%) and ceftriaxone (97.7%), whereas only 53.9%, 63.9%, and 80.4% of isolates were susceptible to macrolides, penicillin (oral), and tetracycline, respectively. LEF also showed potent activity against Staphylococcus aureus (MIC50/90 of 0.06/0.12 µg/mL), including methicillin-resistant (MRSA) isolates (MIC50/90 of 0.06/0.12 µg/mL, 87.1% resistant to erythromycin), Haemophilus influenzae, (MIC50/90 of 0.5/1 µg/mL, 26.9% β-lactamase producing), and Moraxella catarrhalis (MIC50/90 0.06/0.06 µg/mL, 96.5% β-lactamase positive) (figure).

Conclusion
LEF displayed potent in vitro activity against a contemporary collection of respiratory pathogens from the United States. LEF was active regardless of resistance phenotype to other antibiotic classes including β-lactams, tetracyclines, or macrolides. These results further support the clinical development of lefamulin for the treatment of CABP or other respiratory tract infections.

Disclosures
S. Paukner, Nabriva: Employee and Shareholder, Salary. R. K. Flamm, Nabriva: Research Contractor, Research grant. S. P. Gelone, Nabriva Therapeutics: Employee, Equity, Shareholder and Salary. Achaogen: Shareholder, Equity, Shareholder. H. S. Sader, Nabriva Therapeutics: Research Contractor, Research support.
1357. A Combination of Itraconazole and Amiodarone Is Highly Effective Against Trypanosoma cruzi Infection of Human Stem Cell-Derived Cardiomyocytes
Authors: Sass Gabriele , Madigan Roy , Bozzi Adriana , Sayed Nazish , Wu Joseph , Stevens David 
Published: November 2018

Abstract

Background
Trypanosoma cruzi is the etiologic agent of Chagas disease, which can result in severe cardiomyopathy. Trypanosoma cruzi is endemic to the Americas, and of particular importance in Latin America. In the United States and other nonendemic countries, rising case numbers have been observed. The only drugs available so far are benznidazole and nifurtimox, which have limited efficacy during chronic infection. We repurposed itraconazole, originally an antifungal, in combination with amiodarone, an antiarrhythmic, with the goal to interfere with Tc infection. Both drugs inhibit sterol synthesis, while amiodarone also inhibits calcium metabolism of Trypanosoma cruzi.

Methods
Human pluripotent stem cells (HiPSC) were differentiated to cardiomyocytes (HiPSC-CM). Vero cells or HiPSC-CM were infected with the T. cruzi trypomastigotes Y strain in the presence of itraconazole and/or amiodarone. After 48 hours, infection and multiplication were evaluated by Giemsa stain. Benznidazole was used as a reference compound. Cell viability was verified by XTT assay.

Results
Itraconazole and amiodarone showed dose-dependent interference with T. cruzi infection of Vero cells or HiPSC-CM. The combination of itraconazole and amiodarone was more potent than the single substances, or benznidazole at therapeutic concentrations, without affecting host cell metabolism. In addition to effects on infection, itraconazole, or amiodarone affected T. cruzi multiplication. Here, itraconazole/amiodarone combinations were more potent than either alone, both, in Vero cells, and HiPSC-CM.

Conclusion
Our in vitro data suggest that a combination of itraconazole and amiodarone might serve as an effective new treatment option for Chagas disease, particularly cardiac involvement, in human and animal patients.

Disclosures
All authors: No reported disclosures.
1364. Efficacy of Omadacycline Against Molecularly Characterized Gram-Positive and Gram-Negative Pathogens Causing Infections in the Phase 3 CABP and ABSSSI Clinical Trials
Authors: Mendes Rodrigo E , Castanheira Mariana , Armstrong Eliana S , Steenbergen Judith N , Flamm Robert K 
Published: November 2018

Abstract

Background
Omadacycline (OMC) is a once-daily agent with IV and oral formulations. One Phase 3 trial for community-acquired bacterial pneumonia (CABP; OPTIC) and two Phase 3 trials for acute bacterial skin and skin structure infections (ABSSSI; OASIS-1 and OASIS-2) were completed. OMC and comparator efficacies were examined for molecularly characterized baseline pathogens.

Methods
Gram-positive (24) and -negative (17) isolates from the OPTIC (26), OASIS-1 (10) or OASIS-2 (5) trials were selected for characterization. Susceptibility testing and interpretation was performed by CLSI methods. Gram-positive isolates were selected based on tetracycline and/or macrolide, lincosamide, streptograminB (MLSB) phenotypes, and tetracycline-nonsusceptible (NS) Gram-negative isolates were selected. Isolates were subjected to next-generation sequencing followed by screening for known tetracycline and/or MLSB genes. The efficacy endpoint was investigator’s assessment of clinical response at post therapy evaluation (PTE).

Results
All S. aureus (eight isolates) exhibited a doxycycline-NS phenotype (MIC, 8–16 µg/mL) and OMC MIC values of 0.25–0.5 µg/mL. All S. aureus carried tet(M), except one isolate with tet(K), and one isolate with tet(M) and tet(L). All but one S. pneumoniae (16 isolates; OMC MIC, 0.03–0.06 µg/mL) carried MLSB genes, while tetracycline- and doxycycline-NS isolates (12) had tet(M). E. coli (eight isolates; OMC MIC, 0.5–2 µg/mL), E. cloacae (two isolates; OMC MIC, 2 µg/mL), and K. pneumoniae (six isolates; OMC MIC, 2–16 µg/mL) carried tetracycline efflux-pump genes, tet(A) and/or tet(B), tet(D), and tet(A), respectively. tet genes were not detected in one K. pneumoniae (OMC MIC, 8 µg/mL). Clinical success was noted in 37/41 (90.2%) patients. Two linezolid-treated patients with S. aureus (OMC MIC, 0.25 µg/mL) from OASIS-1 and one OMC-treated patient from OPTIC with E. coli (OMC MIC, 2 µg/mL) had indeterminate PTE responses. One OMC-treated patient from OPTIC with K. pneumoniae (OMC MIC, 8 µg/mL) was a clinical failure at PTE.

Conclusion
This study expands on OMC efficacy data analysis among patients infected with tetracycline–NS pathogens. These results indicate that OMC in vivo efficacy is not affected by tetracycline and/or MLSB resistance mechanisms.

Disclosures
R. E. Mendes, Paratek Pharmaceuticals: Research Contractor, Research support. M. Castanheira, Paratek Pharmaceuticals: Research Contractor, Research support. E. S. Armstrong, Paratek Pharmaceuticals: Employee, Salary. J. N. Steenbergen, Paratek Pharmaceuticals: Employee and Shareholder, Salary. R. K. Flamm, Paratek Pharmaceuticals: Scientific Advisor, Speaker honorarium.
1365. In Vitro Activity of Lefamulin (LEF) Against Bacterial Pathogens Causing Community-Acquired Bacterial Pneumonia (CABP): SENTRY Surveillance 2016 Results From Asia-Pacific (APAC) and Latin America (LA)
Authors: Paukner Susanne , Flamm Robert K , Gelone Steven P , Sader Helio S 
Published: November 2018

Abstract

Background
LEF, a novel pleuromutilin antibiotic for IV and oral use, recently completed a phase 3 trial for the treatment of CABP in adults where it demonstrated noninferiority to moxifloxacin ± linezolid. LEF selectively inhibits bacterial translation. This study investigated the activity of LEF and comparators against contemporary bacterial respiratory pathogens collected from APAC and LA.

Methods
Unique isolates were collected from patients with pneumonia/respiratory (n = 551), blood stream (n = 169), skin and soft tissue (n = 244), and other (n = 55) infections in seven countries in APAC (n = 587) and four countries in LA (n = 432). LEF and comparators were tested by CLSI broth microdilution methods, and susceptibility was determined using CLSI (2018) breakpoints.

Results
In both APAC and LA, LEF showed potent in vitro activity against this collection of respiratory pathogens, with 100% of Streptococcus pneumoniae inhibited at ≤0.25 μg/mL. S. pneumoniae isolates were largely susceptible to moxifloxacin (98.2% APAC, 100.0% LA), amoxicillin/clavulanic acid (84.3% APAC, 89.4% LA), and ceftriaxone (85.2% APAC, 93.6% LA), but less susceptible to azithromycin (56.6% APAC, 68.1% LA) and penicillin (48.2% APAC, 67.0% LA). LEF was also active against Staphylococcus aureus with 99.6% of all isolates from both APAC and LA being inhibited at 0.25 µg/mL. 29.5% of methicillin-resistant S. aureus in APAC and 24.7% in LA showed particularly high resistance rates to erythromycin (59.3% APAC, 64.2% LA), moxifloxacin (49.4% APAC, 53.7% LA), and clindamycin (39.5% APAC, 59.7% LA). 98.2% and 97.9% of Haemophilus influenzae (in APAC and LA, respectively) were inhibited at LEF ≤2 μg/mL, and 100.0% of Moraxella catarrhalis were inhibited at LEF ≤0.12 μg/mL in both APAC and LA. Both organisms were largely susceptible to the comparators, except for ampicillin (49.1% and 74.5% susceptible among H. influenzae in APAC and LA, respectively) and trimethoprim/sulfamethoxazole (54.4% and 68.1% susceptible among H. influenzae) (figure).

Conclusion
In APAC and LA, LEF was highly active against pathogens collected from CABP patients in 2016, and its activity was not affected by resistance to other antibiotic classes. These data support the ongoing development of LEF for the treatment of CABP.

Disclosures
S. Paukner, Nabriva: Employee and Shareholder, Salary. R. K. Flamm, Nabriva Therapeutics: Research Contractor, Research support. S. P. Gelone, Nabriva Therapeutics: Employee, Equity, Shareholder and Salary. Achaogen: Shareholder, Equity, Shareholder. H. S. Sader, Nabriva Therapeutics: Research Contractor, Research support.
1366. In Vitro and In Vivo Activity of Cefiderocol against Stenotrophomonas maltophilia Clinical Isolates
Authors: Ito Akinobu , Ota Merime , Nakamura Rio , Tsuji Masakatsu , Sato Takafumi , Yamano Yoshinori 
Published: November 2018

Abstract

Background
Cefiderocol (S-649266, CFDC) is a novel siderophore cephalosporin against Gram-negatives, including carbapenem (CR)-resistant strains. Its spectrum includes both the Enterobacteriaceae but also nonfermenters, including Stenotrophomonas maltophilia—an opportunistic pathogen with intrinsic resistance to carbapenem antibiotics. In this study, in vitro activity and in vivo efficacy of CFDC and comparators against S. maltophilia were determined.

Methods
MICs of CFDC and comparators (trimethoprim/sulfamethoxazole (TMP/SMX), minocycline (MINO), tigecycline (TGC), ciprofloxacin (CPFX), cefepime (CFPM), meropenem (MEPM), and colistin (CL)) were determined by broth microdilution method as recommended by CLSI. The MIC against CFDC was determined using iron-depleted cation-adjusted Mueller–Hinton broth. In vivo efficacy of CFDC, CFPM, ceftazidime–avibactam (CAZ/AVI), MEPM, and CL was evaluated using neutropenic murine systemic infection model caused by strain SR21970. The 50% effective doses (ED50s) were calculated by the logit method using the survival number at each dose 7 days after infection.

Results
MIC90 of CFDC and comparators against the 216 clinical isolates from global countries collected in SIDERO-CR 2014/2016 study are shown in the table. CFDC, TMP/SMX, MINO, and TGC showed good activity with MIC90 of 0.5, 0.25/4.75, 1, and 2 µg/mL, respectively. CFDC, MINO, and TGC inhibited growth of all tested strains at ≤1, ≤4, and ≤8 µg/mL although two strains showed resistance to TMP/SMX. MICs of CFPM, CAZ/AVI, MEPM, and CL were ≥32 µg/mL. The ED50 of CFDC against S. maltophilia SR21970 with MIC of 0.125 mg/mL was 1.17 mg/kg/dose. Conversely, MICs of CFPM, CAZ/AVI, MEPM/CS, and CL against SR21970 were 32 μg/mL or higher, and ED50s were &gt;100 mg/kg/dose, showing that CFDC had potent in vivo efficacy against S. maltophilia strain which was resistant to other antibiotics.

Conclusion
CFDC showed potent in vitro activity against S. maltophilia, including TMP/SMX-resistant isolates. CFDC also showed potent in vivo efficacy reflecting in vitro activity against S. maltophilia in murine systemic infection model.

Disclosures
A. Ito, Shionogi & Co., Ltd.: Employee, Salary. M. Ota, Shionogi & Co., Ltd.: Employee, Salary. R. Nakamura, Shionogi & Co., Ltd.: Employee, Salary. M. Tsuji, Shionogi & Co., Ltd.: Employee, Salary. T. Sato, Shionogi & Co., Ltd.: Employee, Salary. Y. Yamano, Shionogi & Co., Ltd.: Employee, Salary.
1369. Combined Analysis of the In Vitro Activity of Ridinilazole (RDZ) Against More Than 500 Clostridium difficile (CD) Clinical Isolates and Impact of RDZ on Cell Morphology
Authors: Duperchy Esther , Bassères Eugénie , Garey Kevin , Vickers Richard 
Published: November 2018

Abstract

Background
Clostridium difficile infection (CDI) is one of the most urgent bacterial healthcare threats in the United States. RDZ is a targeted spectrum, GI restricted, antibacterial currently in clinical development for the treatment of CDI and reducing the recurrence of CDI. Here we report the combined analysis of previously reported and new independent studies assessing the susceptibility of CD clinical isolates collected in North America and Europe between 2010 and 2015, and the effect of RDZ on cell morphology.

Methods
A total of 570 CD clinical isolates across seven independent studies were tested for susceptibility. The majority of isolates (&gt;70%) were sourced from RDZ Phase 2 clinical trials and North American and European surveillance programs. Minimum inhibitory concentrations (MIC) were determined by agar dilution on Wilkins Chalgren agar plates after 48 hours incubation at 37oC, or, by agar or microbroth dilution using supplemented Brucella medium following the CLSI guidelines M11-A7/A8. Up to 11 comparator antibiotics were tested alongside RDZ. PCR ribotyping was performed on 549 isolates by capillary gel electrophoresis. To investigate the impact of RDZ on cell morphology, CD strain R20291 was incubated with RDZ at 0.125–0.5 × MIC concentrations for 24 hours. DAPI and FM4-64 staining was used to visualize DNA and cell membrane by confocal microscopy.

Results
RDZ was highly active against the isolates collected in North America and Europe with MICs distributed over a narrow range (0.015–0.5 μg/mL) and an overall MIC90 of 0.25 μg/mL. There was no variation in activity by geographic region or ribotype, including hypervirulent ribotype 027 isolates (N = 83). RDZ also maintained activity against antibiotic-resistant isolates, including isolates with reduced susceptibility to metronidazole and vancomycin. When treated with sub-MIC concentrations of RDZ, CD cells formed filamentous structures with a dose-dependent effect on cell length and decreased septum formation. This preliminary data suggest that RDZ may alter CD cell division.

Conclusion
These data show that RDZ was highly active against recent CD isolates independent of geographic origin, ribotype, and antibiotic resistance profile. Mechanism of action studies are ongoing and further susceptibility profiling will be undertaken during the Phase 3.

Disclosures
E. Duperchy, Summit Therapeutics: Employee, Salary. E. Bassères, Summit Therapeutics: Collaborator, Research support. K. Garey, Summit Therapeutics: Collaborator, Research support. R. Vickers, Summit Therapeutics: Employee, Salary and Stock options.
1372. In Vitro Activity of Novel Ceftazidime–Avibactam and Aztreonam–Avibactam Combinations Against Carbapenem-Nonsusceptible Enterobacteriaceae Isolates by Phenotype Collected in Latin America From 2014 to 2017 as Part of the INFORM Surveillance Program
Authors: Kazmierczak Krystyna , De Jonge Boudewijn , Stone Gregory G , Sahm Dan 
Published: November 2018

Abstract

Background
Carbapenem-nonsusceptible Enterobacteriaceae (CRE) are often multidrug-resistant and infections caused by these organisms are associated with increased morbidity and mortality. The combination of avibactam (AVI), a non-β-lactam/β-lactamase inhibitor of Class A, C, and some D serine β-lactamases, with ceftazidime (CAZ) and aztreonam (ATM) is being developed to treat infections caused by CRE. CAZ-AVI reveals potent in vitro activity against CRE, except those producing metallo-β-lactamases (MBLs), whereas ATM-AVI inhibits growth of both MBL-positive and MBL-negative CRE. We evaluated the in vitro activity of CAZ-AVI and ATM-AVI against Enterobacteriaceae isolates nonsusceptible to meropenem (MEM-NS) collected in 2014–2017 in Latin America through the INFORM global surveillance program.

Methods
Nonduplicate clinically significant isolates were collected from 29 hospital laboratories located in Argentina, Brazil, Chile, Colombia, Mexico, and Venezuela. Susceptibility testing was performed by CLSI broth microdilution. AVI was tested at a fixed concentration of 4 µg/mL in combination with CAZ and ATM. MEM-NS Eba (MIC &gt;1 µg/mL) were screened for the presence of β-lactamase genes by PCR and sequencing.

Results
Five hundred fifty-seven MEM-NS isolates were identified (440 Klebsiella pneumoniae and 117 isolates of 13 other species). Of these, 441 (79.2%) carried carbapenemases (Cpase) (KPC only, n = 383; MBL only, n = 48; OXA-48-like only, n = 5; KPC and OXA-48-like, n = 2; MBL and GES, n = 2; MBL and KPC, n = 1). CAZ-AVI showed potent in vitro activity against Cpase-positive MBL-negative and Cpase-negative Eba and against all MEM-NS Eba, but was not active against MBL-positive Eba. 100% of MEM-NS Eba were inhibited by ≤8 µg/mL of ATM-AVI.

Conclusion
CAZ-AVI and ATM-AVI displayed potent in vitro activity against MEM-NS Eba collected in LA. These agents could serve as promising options for treatment of infections caused by CRE.

Disclosures
K. Kazmierczak, Pfizer Inc.: Consultant, Consulting fee. IHMA, Inc.: Employee, Salary. B. De Jonge, AstraZeneca: Shareholder, Dividends. Pfizer Inc: Employee, Salary. G. G. Stone, Pfizer Inc.: Employee, Salary. AstraZeneca: Former Employee and Shareholder, Salary. D. Sahm, Pfizer Inc.: Consultant, Consulting fee.
IHMA, Inc.: Employee, Salary.
1375. In vitro Activity of Cefiderocol and Comparator Agents against Gram-Negative Isolates from Cancer Patients
Authors: Rolston Kenneth V I , Gerges Bahgat , Raad Issam , Aitken Samuel L , Reitzel Ruth , Prince Randall 
Published: November 2018

Abstract

Background
Gram-negative bacilli (GNB) are now the predominant cause of bacterial infection in cancer patients (CP). Many GNB are problematic because they have become resistant to commonly used antibiotics. Cefiderocol (CFDC), a novel siderophore cephalosporin, is active against a wide spectrum of GNB. We evaluated its in vitro activity and that of eleven comparator agents against GNB isolated from CP.

Methods
A total of 341 recent GNB blood isolates from CP were tested using CLSI approved methods for MIC determination by broth microdilution. Comparator agents were amikacin (A), aztreonam (AZ), ceftazidime (CZ), ceftazidime/avibactam (CAV), cefepime (CEF), ciprofloxacin (CIP), colistin (CL), meropenem (MR), ceftolozane/tazobactam (C/T), tigecycline (TG), and trimethoprim/sulfamethoxazole (T/S).

Results
CFDC MIC90s as mg/L were: S. maltophilia [50 isolates] 0.25, E. coli (ESBL−) [50 isolates] 0.5, E. coli (ESBL+) [51 isolates] 2.0, K. pneumoniae (ESBL− and +) [60 isolates] 0.5; K. pneumoniae (CRE) [22 isolates] 2.0; P. aeruginosa (MDR) [32 isolates] 1.0; E. cloacae [27 isolates] 4.0; Achromobacter spp. [15 isolates] 0.12. CFDC inhibited P. agglomerans, Burkholderia spp., Sphingomonas spp., Ochrobactrum spp. at ≤1 mg/L [23 total isolates] and Elizabethkingia spp. and R. radiobacter at ≤8 mg/L [11 total isolates]. Among comparator agents, only T/S had consistent activity against S. maltophilia. For E. coli (ESBL− and +) MR, TG, CAV, CL were most active. For K. pneumoniae (ESBL–and +) MR, CAV were most active. For K. pneumoniae (CRE) and P. aeruginosa (MDR), none of the comparators had significant activity. For E. cloacae, MR, A, CAV, TG were most active. Among the uncommon organisms, MR and TG had the greatest activity.

Conclusion
Although susceptibility breakpoints have yet to be determined, CFDC has significant activity (≤4 mg/L) against most problematic Gram-negative organisms causing infections in CP based on available pharmacokinetic/pharmacodynamic data. In particular, its activity against S. maltophilia was superior to the comparators. Also, it was the most active agent against P. aeruginosa (MDR) and K. pneumoniae (CRE). Based on our results, CFDC warrants clinical evaluation for the treatment of blood stream infections caused by GNB in CP.

Disclosures
K. V. I. Rolston, Merck: Investigator, Research grant; JMI Laboratories: Investigator, Research grant; Shionogi (Japan): Investigator, Research grant. B. Gerges, Shionogi: Collaborator, Research support. S. L. Aitken, Shionogi: Scientific Advisor, Consulting fee; Merck: Scientific Advisor, Consulting fee; Medicines Co: Scientific Advisor, Consulting fee; Achaogen: Scientific Advisor, Consulting fee; Zavante: Scientific Advisor, Consulting fee; R. Prince, Shionogi: Investigator, Research support. Merck: Investigator, Research support.