bluuebunny/crossref_metadata_2025 huggingface dataset:
1338. A Pooled Analysis of Patients With Wound Infections in the Phase 3 REVIVE Trials: Randomized, Double-blind Studies to EValuate the Safety and Efficacy of Iclaprim Vs. Vancomycin for trEatment of Acute Bacterial Skin and Skin Structure Infections
Authors: Huang David , Corey G Ralph , Holland Thomas L , Lodise Thomas P , O’Rirodan William , Wilcox Mark , File Thomas M , Dryden Matthew , Torres Antoni , Balser Barbara , Desplats Eve
Published: November 2018

Background

The objective of this evaluation was to provide an analysis of pooled efficacy data from two parallel Phase 3 trials of iclaprim, a diaminopyrimidine dihydrofolate reducatase inhibitor, compared with vancomycin for the treatment of patients with wound infections including surgical site infections (SSI).

Methods

A pooled analysis of patients with wound infections was conducted from two parallel Phase 3, double-blind, randomized (1:1), active-controlled, multinational, multicenter trials (REVIVE-1 and REVIVE-2), which included a total of 602 patients with wound infections. The data were analyzed separately and then pooled to determine the efficacy of iclaprim 80 mg fixed dose compared with vancomycin 15 mg/kg. Both drugs were administered intravenously every 12 hours for 5 to 14 days according to the investigator assessment of clinical response. The primary endpoint of these studies was to determine whether iclaprim was noninferior (NI; 10% margin) to vancomycin in achieving a ≥20% reduction in lesion size (early clinical response [ECR] at 48 to 72 hours after initiation of the study drug (early time point [ETP]), compared with baseline in the intent-to-treat (ITT) population.

Results

Iclaprim had similar ECR rates at ETP compared with vancomycin among the subset of patients with wound infections (see table). The median treatment duration for both iclaprim and vancomycin was 7 days (range 5–14 days).

Conclusion

In this post-hoc analysis of the REVIVE studies, iclaprim achieved NI to vancomycin in both studies, based on ECR at ETP, in the subgroup of patients with wound infections. These results suggest that iclaprim may be a valuable treatment option for patients with wound infections, including SSI, suspected or confirmed to be due to Gram-positive pathogens.

Disclosures

D. Huang, Motif BioSciences: Employee, Salary. G. R. Corey, Motif BioSciences: Board Member, Consulting fee. T. L. Holland, Basilea: Consultant, Consulting fee. Motif Bio: Consultant and Scientific Advisor, Consulting fee. Theravance: Consultant, Speaker honorarium. Genentech: Consultant, Consulting fee. T. P. Lodise Jr., Motif BioSciences: Board Member, Consulting fee. W. O’Rirodan, Motif BioSciences: Board Member, Consulting fee. M. Wilcox, Motif BioSciences: Board Member, Consulting fee. T. M. File Jr., Motif BioSciences: Board Member, Consulting fee. M. Dryden, Motif BioSciences: Board Member, Consulting fee. B. Balser, Motif BioSciences: Consultant, Consulting fee. E. Desplats, Motif BioSciences: Consultant, Consulting fee.
1340. Population Pharmacokinetic (PK) Analysis of APX001 Using Phase 1 Data
Authors: Trang Michael , Bader Justin C , Ople Eric A , Kramer William G , Hodges Michael R , Bhavnani Sujata M , Rubino Christopher M
Published: November 2018

Background

APX001 is a novel antifungal agent which is rapidly converted to the active metabolite APX001A. APX001A exhibits in vitro activity against many clinically important yeast and fungi, including echinocandin- and azole-resistant Candida species. Given this activity, intravenous (IV) and oral (PO) formulations of APX001 are being developed for the treatment of patients with candidemia or invasive candidiasis. Phase 1 data were used to develop a population PK (PPK) model to describe the time-course of APX001A in plasma.

Methods

The PPK model was developed using 3,736 plasma PK samples collected from 128 healthy subjects who received APX001 single and multiple IV and PO doses ranging from 10 to 1,000 mg. Instantaneous conversion was assumed by scaling input doses by the molecular weight ratio of APX001A to APX001. After development of the structural PK model, stepwise forward and backward selection procedures were used to identify significant covariate relationships. Model qualification included standard goodness-of-fit metrics and prediction-corrected visual predictive check (PC-VPC) plots.

Results

A two-compartment model with zero-order IV input, or first-order PO absorption with lag time to account for the apparent delay in oral absorption, best described APX001A plasma PK. Exponential error models were used to estimate interindividual variability (IIV) for all parameters. Interoccasion variability was estimated for the absorption rate constant, bioavailability, and lag time. Body weight was identified as a statistically significant predictor of the IIV on the volume of the central and peripheral compartments. The PPK model provided an accurate and unbiased fit to the plasma data based on individual- and population-predicted concentrations (r2 = 0.977 and 0.873, respectively). The PC-VPC plots for the final PPK model (Figure 1) demonstrated good alignment between observed concentrations and the model predicted 5th, 50th, and 95th percentiles.

Conclusion

A PPK model describing APX001A plasma PK following IV or PO doses was successfully developed. This model will be useful for generating simulated APX001A exposures for use in pharmacokinetic–pharmacodynamic target attainment analyses to support APX001 dose selection.

Disclosures

M. Trang, Amplyx Pharmaceuticals, Inc.: Research Contractor, Research support. J. C. Bader, Amplyx Pharmaceuticals, Inc.: Research Contractor, Research support. E. A. Ople, Amplyx Pharmaceuticals, Inc.: Employee, Salary. W. G. Kramer, Amplyx Pharmaceuticals, Inc.: Scientific Advisor, Consulting fee. M. R. Hodges, Amplyx Pharmaceuticals, Inc.: Employee, Salary. S. M. Bhavnani, Amplyx Pharmaceuticals, Inc.: Research Contractor, Research support. C. M. Rubino, Amplyx Pharmaceuticals, Inc.: Research Contractor, Research support.
1346. The Tetrazole VT-1598 Is Efficacious in a Murine Model of Invasive Aspergillosis with a PK/PD Expected of a Mold-Active CYP51 Inhibitor
Authors: Garvey Edward P , Sharp Andrew , Warn Peter , Yates Christopher M , Schotzinger Robert J
Published: November 2018

Background

VT-1598 is a novel fungal CYP51 inhibitor with potent in vitro activity against yeast, mold, and endemic pathogenic fungi (Wiederhold, JAC, 2017). Its tetrazole-based rational drug design imparts much greater selectivity vs. human CYPs (Yates, BMCL, 2017), which could reduce human CYP-related side effects and DDIs. We report here VT-1598’s in vivo activity in an invasive aspergillosis (IA) model.

Methods

MIC was determined as outlined in CLSI M38-A2. Plasma PK was measured after 4 days of oral doses in neutropenic ICR mice without fungal inoculation. In vivo antifungal activity was determined in a tail-vein IA model in neutropenic mice inoculated with A. fumigatus (AF) ATCC 204305 (N = 10 per dose). Two separate studies were conducted, with oral VT-1598 treatment starting either 48 hours prior (prophylaxis) or 5 hours postinoculation (delayed), with 4 days of postinoculation dosing, and kidney fungal burden measured 1 day post last dose by both CFU and qPCR. Drug control was 10 mg/kg AmBisome i.v.

Results

The MIC for VT-1598 against AF 204305 was 0.25 μg/mL. The plasma PK of VT-1598 was linearly proportional between the 5 and 40 mg/kg once-daily doses, with AUCs of 155 and 1,033 μg h/mL for the two doses, respectively. VT-1598 was similarly effective in reducing fungal burden when given in delayed treatment compared with prophylaxis, and both studies demonstrated a full dose–response (i.e., no to full reduction of fungal burden). When comparing fungal burdens of each dose group to the fungal burden at the start of treatment, the dose of VT-1598 to achieve fungal stasis ranged from 20.5 to 25.9 mg/kg and to achieve a 1-log10 fungal kill ranged from 30.9 to 50.5 mg/kg. Using the previously measured mouse plasma binding (>99.9%), the free AUC /MIC values for stasis and 1-log10 kill ranged from 2.1–2.7 and 3.2–5.2, respectively. These values are within the range of 1–11 that have been reported for posaconazole and isavuconazole (Lepak, AAC, 2013).

Conclusion

VT-1598 had potent antifungal activity in a murine model of IA. The PK/PD relationship was the same as clinically used mold-active CYP51 agents, suggesting that it could have similar clinical efficacy. If correct, the tetrazole-based greater selectivity may significantly differentiate VT-1598 from current IA therapies.

Disclosures

E. P. Garvey, Viamet Pharmaceuticals, Inc.: Employee, Salary. A. Sharp, Evotec (UK) Ltd.: Employee, Salary. P. Warn, Evotec (UK) Ltd.: Employee, Salary. C. M. Yates, Viamet Pharmaceuticals, Inc.: Employee, Salary. R. J. Schotzinger, Viamet Pharmaceuticals, Inc.: Board Member and Employee, Salary.
1349. Global Surveillance of Cefiderocol Against Gram-Negative Clinical Strains Collected in North America: SIDERO-WT-2015
Authors: Tsuji Masakatsu , Hackel Meredith , Echols Roger , Yamano Yoshinori , Sahm Dan
Published: November 2018

Background

Cefiderocol (CFDC) is a novel parenteral siderophore cephalosporin with potent activity against a wide range of Gram-negative pathogens, including carbapenem-resistant strains. Additionally, a recently conducted in vivo murine-based study has demonstrated an incremental exposure-response profile over a dose range without the appearance of adaptive resistance. In this study, we evaluated the in vitro activity of CFDC and comparator agents against clinical isolates collected in 2015–2016 from North America from SIDERO-WT-2015 surveillance study.

Methods

A total of 3,602 isolates (2,470 Enterobacteriaceae, 223 A. baumannii, 85 Acinetobacter spp., 619 P. aeruginosa, 165 S. maltophilia and 17 Burkholderia cepacia, and 23 Burkholderia spp.) collected from the United States and Canada in 2015–2016 were tested. MICs were determined for CFDC, cefepime (FEP), ceftazidime–avibactam (CZA), ceftolozane–tazobactam (C/T), ciprofloxacin (CIP), colistin (CST), and meropenem (MEM) by broth microdilution and interpreted according to CLSI guidelines. As recommended by CLSI, cefiderocol was tested in iron-depleted cation-adjusted Mueller–Hinton broth (ID-CAMHB). Carbapenem nonsusceptible (Carb-NS) strains were defined as MEM MIC ≥2 µg/mL for Enterobacteriaceae, and ≥4 µg/mL for nonfermenters.

Results

CFDC exhibited potent in vitro activity against 3,602 strains of Gram-negative bacteria with an overall MIC90 of 0.5 mg/mL. As shown in the following table, MIC90 of CFDC against P. aeruginosa, A. baumannii, S. maltophilia, and Enterobacteriaceae including the subset of Carb-NS isolates were 0.5, 2, 0.5 and 0.5 mg/mL, respectively. At 4 mg/mL, CFDC inhibited the growth of 99.6% of the isolates while 18.1%, 12.6%, and 13.8% showed resistance to CZA, C/T, and CST, respectively.

Conclusion

CFDC demonstrated potent in vitro activity against the teat isolates collected from North America with greater than 99.6% of isolates having MIC values ≤4 mg/mL, including Carb-NS isolates of A. baumannii, P. aeruginosa, and Enterobacteriaceae. These findings indicate that this agent has high potential for treating infections caused by these problematic organisms.

Disclosures

M. Tsuji, Shionogi & Co., Ltd.: Employee, Salary. M. Hackel, IHMA, Inc.: Employee, Salary. Y. Yamano, Shionogi & Co., Ltd.: Employee, Salary. D. Sahm, IHMA, Inc.: Employee, Salary.
1352. A Computational Approach for Exploring the Binding Mechanism of Chebulinic Acid on Herpes Simplex Virus-2 and Its Implication on Chikungunya and Dengue
Authors: Thomas Naiju , Kumar Sandeep , Kumar Vikas , Tapryal Suman
Published: November 2018

Background

Chebulinic acid (CA), a natural compound isolated from the tree Terminalia chebula, was recently reported to have shown antiviral activity against Herpes simplex virus-2 (HSV-2). The study showed inhibition activity of CA, preventing the attachment of HSV-2 on the host cells. This activity was speculated to be due to an interaction between CA and viral surface glycoproteins, triggering alterations in its function or making virus particles inert and preventing their attachment to host cells. However, the mechanism of this inhibition was not established. The current study was designed not only to help gain insights of the mechanism of action of CA on HSV-2, but also to computationally check its binding affinity on other enveloped arboviruses, i.e., Chikungunya (ChikV) and Dengue (DenV).

Methods

The viral surface glycoproteins of HSV-2, ChikV, and DenV were subjected to molecular docking with CA using the software, AutoDock Vina. Protein–protein docking was performed with ClusPro online server to elucidate the specific site and residues involved in binding between viral protein and human host receptors. Due to unavailability of crystal structure of Prohibitin, a human receptor for ChikV, structural modeling was performed with i-Tasser server.

Results

The conformations obtained after docking showed good hydrogen bond interactions with a docking energy of −9.3, −8.1, and −8.8 kcal/mol against HSV-2, ChikV, and DenV, respectively. In all three viruses, CA was found to bind specifically at the site directly involved in host attachment, suggesting a possible mechanism of action by which CA inhibits the viral attachment that is consistent with the result obtained from the in vitro experiment on HSV-2. Hence the natural bio-molecule Chebulinic acid has the potential to inhibit the host attachment step of HSV-2, ChikV, and DenV by directly binding to their viral glycoproteins.

Conclusion

Chebulinic acid shows a good propensity as an antiviral agent, capable of acting against multiple enveloped viruses. Additionally, a more potent and specific drug can be designed on the template of CA by process of molecular modification.

Disclosures

N. Thomas, Department of Science and Technology: Government of India funding agency, Salary. S. Kumar, University Grants Commission: Government of India funding agency, Educational grant. V. Kumar, University Grants Commission: Government of India funding agency, Educational grant. S. Tapryal, Department of Science and Technology: Government of India funding agency, Research grant.
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

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

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

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

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

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 >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

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 (>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

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 >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

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.
1383. In vivo Pharmacokinetic/Pharmacodynamic (PK/PD) Evaluation of NOSO-502, a First-in-Class Odilorhabdin Antibiotic, Against E. coli (EC) and K. pneumoniae (KPN) in the Murine Neutropenic Thigh Model
Authors: Zhao Miao , Lepak Alexander J , Andes David R
Published: November 2018

Background

NOSO-502 is a novel, first-in-class Odilorhabdin antibiotic targeting bacterial protein translation, with potent in vitro activity against Enterobacteriaceae including strains with MDR or CRE-phenotype. The goal of this study was to determine the PK/PD characteristics of NOSO-502 using the murine thigh infection model against a diverse group of EC and KPN strains.

Methods

Twelve strains (6 EC, 6 KPN) were utilized, including those with tetracycline or β-lactam resistance. MICs were determined by CLSI Methods. Single dose murine plasma PK of NOSO-502 was determined after administration of 7.81, 31.25, 125 and 500 mg/kg by SC route. Dose fractionation (DF) study was used to determine which PK/PD index was associated with efficacy. The relationship between each PK/PD indices and CFU outcome data were analyzed using the sigmoid Emax (Hill) model with nonlinear regression. Treatment studies were then performed with the remaining 11 strains. Four-fold increasing NOSO-502 doses (3.91–1,000 mg/kg/6 hours SC route) were administered. Treatment data and AUC/MIC was analyzed to determine AUC/MIC targets associated with net stasis and 1-log kill (when achieved) for all strains.

Results

MICs ranged from 1 to 4 mg/L. PK ranges for doses included: Cmax 1.5–85 mg/L, AUC0-∞ 1.9–352 mg hour/L, T1/2 0.4–1.1 hour. DF regression analysis: AUC/MIC R2 0.86, Cmax/MIC R2 0.70, T > MIC R2 0.77. Against each of the 12 strains there was dose-dependent activity and net stasis was achieved against all strains, with maximal activity of 1–2 log killing in EC and almost 3 log killing in KPN. The 24 hours stasis total and free drug PD targets are shown (table). 1-log kill targets were determined for KPN and noted at a median 24 hours fAUC/MIC of 11.

Conclusion

NOSO-502 demonstrated in vivo potency against a diverse group of EC and KPN strains including those with resistance to tetracycline and β-lactams. The PK/PD index predictive of efficacy is AUC/MIC. Stasis 24 hours AUC/MIC targets were numerically low for KPN and EC. This data suggest that NOSO-502 is a promising novel agent and these targets will provide a basis for developing human dosing regimens to optimize efficacy.

Disclosures

M. Zhao, Nosopharm: Research Contractor, Research support. A. J. Lepak, Nosopharm: Research Contractor, Research support. D. R. Andes, Nosopharm: Research Contractor, Research support.
1394. A Translational Pharmacokinetic Rat Model of Cerebral Spinal Fluid (CSF) and Plasma Concentrations of Cefepime
Authors: Liu Jiajun , Avedissian Sean , Pais Gwendolyn , Joshi Medha , Rhodes Nathaniel J , Scheetz Marc H
Published: November 2018

Background

For treatment of central nervous system infections caused by GNB, adequate cefepime concentrations are required in the cerebral spinal fluid (CSF) and brain. However, high plasma cefepime exposures have resulted in neurotoxicity. There is a need to understand the real-time pharmacokinetic (PK) relationship between plasma and CSF concentrations as serial CSF sampling is not regularly performed.

Methods

Male Sprague-Dawley rats received cefepime via an internal jugular vein catheter. A total daily dose of 150 mg/kg/day was administered as a single injection every 24 hours for 4 days. Plasma samples (mean n = 5 per rat) was obtained via a second dedicated catheter, with up to five samples obtained on a single concentration–time curve. CSF sampling occurred via an intracisternal catheter, with up to two samples taken every 24 hours. Cefepime in plasma and CSF were quantified via LC–MS/MS. PK analyses were conducted using Pmetrics for R. Multiple physiologic compartmental models were fit, with the ultimate model selected by Akaike score and rule of parsimony. Each rat’s concentrations were predicted from the final model, and predictive performance was evaluated with bias and imprecision of the population and Bayesian posterior prediction models. PK parameters were estimated, and PK exposures during the first 24 hours (i.e., AUC0–24, CMAX0–24, CMIN0–24) were calculated for each rat from Bayesian posteriors.

Results

Eleven rats contributed PK data. A three-compartment model fit the data well [Figure 1: Plasma, Population (a) and Bayesian (b); Figure 2: CSF, Population (a) and Bayesian (b)]. Population median parameter values (CV%) for rate constant (Ke), volume central compartment (V1), volume CSF compartment (V3), rate to/from central/peripheral compartment (KCP, KPC), rate to/from central/CSF compartment (K13, K31) were: 5.04 hour−1 (43.4%), 0.069 L (39.24%), 0.28 hour−1 (52.11%), 17.42 hour−1(34.83%), 0.32 hour−1 (165.3), 0.31 hour−1 (79.89), respectively. Noncompartmental analysis of the Bayesian posteriors revealed a plasma median half-life, AUC0–24, CMAX0–24, and CMIN0–24 of 2.6 hours, 158.1 mg hour/L, 189.3 mg/L, and 0.0003 mg/L from the first dose.

Conclusion

Cefepime transit to the CSF is rapid and highly predictable in the rat model. This model will be highly useful for understanding neurotoxicity outcomes for cefepime.

Disclosures

J. Liu, Merck: Grant fund from Merck, Research grant.
1397. Comparative Efficacy of Human-Simulated Epithelial Lining Fluid (ELF) Exposures of Tedizolid (TZD) Against Methicillin-resistant Staphylococcus Aureus (MRSA) in Neutropenic (I−) vs. Immunocompetent (I+) Murine Models of Pneumonia
Authors: Kidd James M , Abdelraouf Kamilia , Nicolau David P
Published: November 2018

Background

TZD is an oxazolidinone with potent in vitro activity against Gram-positive pathogens, including MRSA. Limited data currently exist on the efficacy of TZD in the presence of neutropenia. Herein, we investigate the comparative efficacy of human-simulated ELF exposures of TZD against MRSA in I− and I+ murine models of pneumonia.

Methods

Four MRSA isolates with TZD broth microdilution MICs of 0.5 mg/L were studied. BALB/c mice in I− groups were made neutropenic with cyclophosphamide. Lungs of I− mice were inoculated intranasally with bacterial suspensions of 107 CFU/mL; a higher inoculum of 109 CFU/mL was required to induce infection in I+ mice. Single daily doses of TZD simulating human ELF exposures after doses of 200 mg q24h were determined in both I+ (40 mg/kg) and I− (32 mg/kg) models. Three hours after inoculation, human-simulated doses of TZD were administered q24h for up to 72 hours while control mice were vehicle dosed. A group of control and another of treatment (n = 6) per isolate were sacrificed at 24, 48, or 72 hours for lung harvest. Bacterial densities were determined by quantitative culture and averaged across all isolates. Mice that succumbed to infection before the scheduled time of sacrifice were included in the next group due for sacrifice. Changes in log10 CFU/lungs at 24 hours were compared with 0 hour controls.

Results

The average bacterial burdens at 0 hour were 5.86 ± 0.21 and 8.10 ± 0.24 log10 CFU/lungs among I− and I+ mice, respectively. At 24 hours, average burdens in control mice were comparable among I− and I+ mice at 7.91 ± 0.62 and 9.01 ± 0.69 log10CFU/lungs, respectively. Mean changes in bacterial density are reported in the table. No I+ control mice survived past 48 hours.

Conclusion

Human-simulated ELF exposures of TZD demonstrated substantial and sustained efficacy in both I− and I+ murine models of pneumonia. These preclinical data utilizing clinically achievable bronchopulmonary exposures suggest that the efficacy of TZD for treatment of MRSA lung infections is not compromised by neutropenic status of the host. Further validation of these findings in patients is warranted.

Disclosures

D. P. Nicolau, Merck: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Speaker honorarium.
344. Post Malaria Neurological Syndrome: A Rare Complication of Malaria
Authors: Yadava Sanjay , Fazili Tasaduq , Laleker Ashley , Poudel Pooja
Published: November 2018

Background

Post malaria neurological syndrome (PMNS) is a rare neurological complication that can occur after recovery from malaria, usually following severe Plasmodium falciparum malaria. A total of 43 cases have been previously reported in the literature.

Methods

We report a patient with neurological symptoms following 1 month of clinical and microbiological resolution of severe falciparum malaria following treatment consistent with PMNS.

Results

A 24-year-old male presented with fever, confusion, dysarthria, and grand mal seizure. His recent medical history was significant for severe falciparum malaria with multiorgan dysfunction, including acute kidney injury after being noncompliant with antimalarial prophylaxis while working for the Peace Corps in Togo prior to falling ill. He fully recovered but still required dialysis, and returned to the United States. He presented to the hospital 1 month after his initial malaria infection. On physical examination, the patient was febrile to 38.9°C, lethargic and responsive only to painful stimuli. Signs of meningismus were absent. Computed tomography of head, abdomen and thorax were unrevealing. Magnetic resonance imaging of the brain revealed a nonspecific focus of signal abnormality in right internal capsule. Cerebral spinal fluid (CSF) analysis revealed WBC of 75/μL, with lymphocytic pleocytosis and elevated protein of 65 mg/dL. CSF bacterial and viral polymerase chain reaction pane and cryptococcal antigen were negative. CSF VDRL was nonreactive. HIV antigen/antibody serology was negative. Blood, CSF, and urine cultures were all negative for growth. Two malaria smears were negative. Initially, he was started on broad spectrum antibiotics, Acyclovir and Coartem which were discontinued following negative laboratory results, and a steroid taper was initiated. His mental status began improving on the second day of the initiation of the steroid taper, and he fully recovered by day 5 of steroid therapy.

Conclusion

In patient with recent medical history of malaria who presents with neuropsychiatric symptoms, clinicians must have a high index of suspicion for PMNS.

Disclosures

All authors: No reported disclosures.