bluuebunny/crossref_metadata_2025 huggingface dataset:
2104. Susceptibility Trends in Antifungal Resistance (STAR) Study: Preliminary Data from A New Prospective Antifungal Surveillance Study
Authors: Ghannoum Mahmoud , Lisa Long , Sheriff Rania , Badal Erika , Lass-Flörl Cornelia , Hawser Stephen
Published: October 2019

Background

The development of new anti-infectives has increased rapidly over the past ten years. The need to support these important, life-saving products has increased as well. The STAR program was developed in 2018 to provide a repository of recent clinical fungal isolates with known susceptibility profiles and to monitor resistance trends over time. STAR reports the susceptibility patterns of the earliest STAR data concerning echinocandins, second-generation triazoles, and fluconazole against clinical Candida albicans and non-albicans strains including C. auris from worldwide sources.

Methods

Clinical isolates of Candida spp. (n = 203, from 2017–2018) from culture KOL investigator sites in the United States, Asia and the EU, were tested. Of these, 203 were isolated from blood or body tissues, and the remaining 11 from miscellaneous sources. Species distribution included mainly C. albicans, C. glabrata, C. krusei, C. lusitaniae, C. parapsilosis, C. tropicalis, and the emerging pathogen C. auris. Antifungals tested were amphotericin B (AMB), anidulafungin (ANID), fluconazole (FLU), isavuconazole (ISA), posaconazole (POS), and voriconazole (VOR). All testing was performed according to CLSI M27-A4 methodology.

Results

Overall, MIC50, MIC90, MIC range and percent susceptibility for each drug are listed in Table 1. Our data showed that for ANID, ISA and POS ≥ 93% of isolates were susceptible. While 84 and 88% were susceptible to FLU and VOR, respectively. Moreover, only 78% of isolates were susceptible to AMB. Interestingly, our data show that C. auris isolates were resistant to at least 1 antifungal with 15% of the C. auris strains (n = 40) showing multidrug resistance.

Conclusion

Ongoing antifungal resistance surveillance like STAR is of utmost importance in order to monitor the efficacy of traditional empirical therapy and for the development of novel antifungal agents. This repository and ongoing STAR study will provide a resource to better support the biopharmaceutical industry’s goals to develop new and more potent antifungal agents. STAR will continue to monitor yeasts and will also include more unusual fungi including Mucor, Rhizopus amongst others.

Disclosures

All authors: No reported disclosures.
2107. Azole Therapeutic Drug Monitoring (TDM) in a Multiracial Cohort with Varied Pharmacogenetics
Authors: Yvonne Zhou Peijun , Peng Lim Tze , Lin Sarah Tang Si , Liew Yixin , Grace Sy. Chua Nathalie , Lim Cheryl , Lee Winnie , Xuan Tan Si , fah Lai oi , Tong Tan Thuan , Hock Tan Ban , Chuan Wong Gee , Hoon Andrea Kwa Lay
Published: October 2019

Background

Voriconazole (VOR) and posaconazole (POS) exhibit wide pharmacokinetic variability. Various factors including race and genetic polymorphisms are at play and this may affect treatment response. We aim to evaluate the utility of VOR/POS TDM among Southeast Asians that are predominantly intermediate/poor VOR metabolizers.

Methods

All adults with VOR/POS TDM performed at our institution from 2015 to 2018 were included. We determined proportion of patients and doses required to achieve TDM targets [(2 – 5.5 mg/L (VOR) or ≥ 0.7 and ≥ 1.0 mg/L (POS prophylaxis and treatment respectively)], and correlate levels with treatment efficacy and safety.

Results

VOR/POS TDM was performed mostly among patients with hematological malignancy or solid-organ transplant (146/174, 83.9%). Less than half (32/70, 45.7%) of patients on VOR achieved target—18 (25.7%) were < 2 mg/L while 20 (28.5%) had levels > 5.5 mg/L. Doses required to achieve TDM target ranged from 1.9–11.4 mg/kg/day. Drug interactions, critically ill state and change in drug formulation were major causes of intra-patient variability. One-fifth (n = 14) experienced transaminitis; corresponding VOR trough levels were 0.5–> 7.5 mg/L. Neurotoxicity was also seen in 3 (4.3%) patients—all 3 had VOR trough ≥ 6.7 mg/L and saw symptom resolution upon dose reduction. There appears to be no association between the achievement of TDM targets and response rates. Majority (81/104, 77.9%) of patients on POS achieved TDM targets. Patients prescribed POS tablet were significantly more likely to attain targets compared with suspension 600 mg/day [19/26 (73.0%) vs. 27/62 (43.5%), P < 0.05] and 800 mg/day [17/26 (65.3%) vs. 4/16 (25.0%), P < 0.05)]. Of 23 with sub-therapeutic levels, 19 (82.6%) responded to dose increase and/or change in acid-reducing agents. Breakthrough infection occurred despite troughs ≥ 0.7 mg/L [5/42 (11.9%) vs. 2/40 (5.0%) when < 0.7 mg/L (P = 0.3)]. Treatment failure was observed in 2 patients (troughs > 1.0 mg/L).

Conclusion

VOR/POS TDM should be implemented in Southeast Asians due to significant unpredictability in dose exposure and potential to avoid need for switch to alternative anti-fungals due to intolerability. Higher POS trough cutoff may be required for effective anti-fungal prophylaxis.

Disclosures

All authors: No reported disclosures.
2118. Antifungal Susceptibility Testing of Clinical Isolates of Aspergillus in Mexico
Authors: Gonzalez-Lara María F , Valenzuela-Almada Maria O , Marina Román-Montes Carla , Piñon-Hernandez Viridiana , Rodriguez Jose , Ponce de Leon Alfredo , Sifuentes-Osornio José , Martinez-Gamboa Areli , Ostrosky-Zeichner Luis
Published: October 2019

Background

Invasive aspergillosis (IA) is a leading cause of morbidity and mortality in immunocompromised hosts. Triazole resistance in Aspergillus fumigatus is emerging globally. We performed antifungal susceptibility testing (AST) in Aspergillus isolates from Mexico and evaluated risk factors associated with 6 week mortality, including the MICs.

Methods

Aspergillus isolates from clinical samples were collected in a tertiary care center from 2014 to 2018. Species-level identification and broth microdilution following the CLSI M38 method were performed. MICs were interpreted according to epidemiological cutoff values. PCR and cyp51A gene sequencing were performed in A. fumigatus isolates with voriconazole (VRC) MIC >1 µg/mL. Data from the medical record were obtained to classify patients according to the MSG/EORTC criteria. The relationship between the MICs and 6-week mortality was described. Multivariate analysis of factors associated with six week mortality was performed.

Results

AST was performed on 85 Aspergillus isolates: 60/85 from patients with IA, 15/85 from patients with Aspergillus colonization, 2 patients with Aspergilloma, 1 with chronic otitis media and 1 with endophtalmitis. Information from 6 patients was unavailable. VRC MIC > 1 µg/mL was found in 3/38 (7.8%) A. fumigatus, from two patients with IA. Both had a TR34/L98H mutation in the cyp51A gene. Amphotericin B (AmB) MICs ≥ 2 were found in 16/49 (32%) A. fumigatus, 10/15 (66%) A. flavus and 1/14 (8%) A. niger. Forty-one patients with IA were treated: 29/41 (71%) with VRC or posaconazole, 7/41 (17%) with AmB and 5 with combination therapy. Overall, 6-week mortality was 30/49 (61.2%) among patients with IA; 2/2 (100%) when VRC MIC >1 µg/mL and 12/19 (63%) when AmB > 2 µg/mL, of which only 4 patients received initial treatment with AmB. Age older than 65 years (OR 11.8; 95% CI 1.14–123) and hepatic failure (OR 7.9; 95% CI 1.22–50.9) were independently associated with 6-week mortality in multivariate analysis.

Conclusion

We found a VRC MIC >1 µg/mL prevalence of 7.8% among A. fumigatus and a high prevalence of AmB MIC ≥ 2 among clinical isolates of Aspergillus in Mexico. Elevated mortality was seen in IA among older patients with hepatic failure. Larger epidemiological studies are warranted.

Disclosures

All authors: No reported disclosures.
2119. Matched-Paired Analysis of Patients Treated for Invasive Mucormycosis—Standard Treatment vs. Posaconazole New Formulations (MoveOn)
Authors: Salmanton-Garcia Jon , Seidel Danila , Koehler Philipp , Mellinghoff Sibylle , Wisplinghoff Hilmar , Vehreschild Jörg , Cornely Oliver , Vehreschild Maria
Published: October 2019

Background

Current first-line (first) antifungal treatment for invasive mucormycosis (IM) consists of liposomal amphotericin B (AMB). Salvage (SAL) treatment options are limited and often based on posaconazole oral suspension (POSsusp). However, with the approval of posaconazole new formulations (POSnew), patients could benefit from improved pharmacokinetics, safety and tolerability. Our aim was to assess the effectiveness of POSnew as first-line and SAL treatments for IM.

Methods

We performed a case-matched analysis with proven or probable IM patients from the FungiScope® Registry. 1st-POSnew and 1st-AMB+POSnew cases were matched with 1st-AMB-based treatment controls, and SAL-POSnew cases were matched with SAL-POSsusp controls. Each case was matched with up to three controls based on severity, hematological/oncological malignancy, surgery and/or renal dysfunction.

Results

Five patients receiving first-line POSnew alone, 18 receiving first-line POSnew combined with AMB, and 22 receiving salvage POSnew were identified. By day 42, favorable response was reported for 80.0% (n = 4/5) of patients receiving first-line POSnew, for 27.8% (n = 5/18) receiving first-line POSnew plus AMB, and for 50.0% (n = 11/22) receiving salvage POSnew. Day-42 all-cause mortality of patients receiving POSnew was lower compared with mortality in their respective controls (20.0% (n = 1/5) in 1st-POSnew vs. 53.3% (n = 8/15) in 1st-AMB; 33.3% (n = 6/18) in 1st-AMB+POSnew vs. 52.0% (n = 26/50) in 1st-AMB; 0.0% (n = 0/22) in SAL-POSnew vs. 4.4% (n = 2/45) in SAL-POSsusp).

Conclusion

In the observed patients, POSnew was effective in terms of treatment response and-associated mortality of IM. POSnew may be an alternative for the treatment of IM.

Disclosures

All authors: No reported disclosures.
2144. Performance of 2019 CLSI Ciprofloxacin Breakpoint Antimicrobial Susceptibility Testing Algorithms for Enterobacteriaceae and Pseudomonas aeruginosa Directly from Positive Blood Culture on the Accelerate Pheno™ System
Authors: Shamsheyeva Alena , Oppermann Niels , Taku Aimee , Ndobegang Anyangatia , Gamage Dulini , Chantell Christina , Humphries Romney
Published: October 2019

Background

The Clinical and Laboratory Standards Institute (CLSI) updated fluoroquinolone breakpoints in 2019 in response to evolving resistance and new outcome data. The performance of updated antimicrobial susceptibility testing (AST) algorithms for ciprofloxacin with the 2019 breakpoints for Enterobacteriaceae and Pseudomonas aeruginosa was evaluated using the Accelerate Pheno™ system with contrived positive blood culture samples compared with broth microdilution (BMD).

Methods

A total of 294 clinical isolates (100 P. aeruginosa, 82 Klebsiella spp., 56 E. coli, 24 Citrobacter spp., 14 Enterobacter spp., 15 Proteus spp., and 3 S. marcescens) were tested with ciprofloxacin. Aliquots of BD BACTEC™ Standard Aerobic media containing healthy donor blood were seeded with 10–100 bacterial cells and incubated until positivity. Aliquots of the positive blood cultures were run using the Accelerate PhenoTest™ BC kit on the Accelerate Pheno™ system according to the manufacturer instructions for use. Results were obtained using an updated ciprofloxacin algorithm and compared with CLSI standard reference BMD. Only samples with valid results with both the Accelerate Pheno™ system and reference BMD were included in analysis. Essential agreement (EA), categorical agreement (CA), very major error (VME), major error (ME) and minor error (mE) rates were calculated using 2019 CLSI breakpoints.

Results

EA and CA for all antimicrobial/organism combinations were >94%. There were 2 MEs (1 K. pneumoniae, 1 C. freundii) and no VMEs.

Conclusion

Results with the new research use only (RUO) algorithms are very good and meet FDA acceptance criteria for AST performance. These data will be submitted to the FDA for clearance, once FDA recognizes the CLSI breakpoints.

Disclosures

All authors: No reported disclosures.
2165. Helicobacter pylori Infections in the Bronx, New York: Whole-Genome Sequencing for Rapid Genotypic Susceptibility Testing
Authors: Rajagopalan Saranathan , Szymczak Wendy , Jacobs William , Behin Daniel , Pan Debra , Levi Michael
Published: October 2019

Background

Susceptibility-guided treatment of H. pylori is superior to empiric therapy. We determined the accuracy of whole-genome sequencing (WGS) compared with phenotypic testing using CLSI/EUCAST breakpoints.

Methods

Thirty-three clinical isolates of H. pylori cultured from gastric biopsies were sequenced with a coverage range between 40x and 80x using Illumina Miseq platform and the reads were assembled and annotated with PATRIC. Phenotypic susceptibility tests were performed using E-test strips under microaerophilic conditions for 72 hours. Mutations associated with amoxicillin, tetracycline, clarithromycin, levofloxacin, metronidazole and rifampin resistance were examined.

Results

Of the 33 isolates, two were phenotypically resistant to amoxicillin: one carried a β-lactamase gene (blaTEM-116) and the other exhibited a point mutation pbp2 (A541T). All isolates were tetracycline susceptible phenotypically, but three isolates had point mutations in 16S rRNA that are associated with resistance (A926G). Clarithromycin results showed a good correlation between methods. Nine clarithromycin-resistant isolates demonstrated point mutations in 23S rRNA (A2142G/A2143G). Fifteen isolates were phenotypically resistant to levofloxacin, but resistance mutations were found in only 14 strains (N87I/N87K/D91Y/D91N/D91G/D99N in gyrA). We analyzed our strains for the presence of intact genes rdxA and frxA, either of which convert the prodrug form of metronidazole into the active form. Twenty-four of 33 isolates were tested phenotypically. We found 3 isolates with truncations in both genes. These isolates had metronidazole MICs >256. The presence of one or both intact genes did not always result in low MICs, indicating that there may be significant point mutations that contribute to resistance. Rifampin was not tested phenotypically, but no mutations in rpoB were found. In summary, the correlation of WGS and phenotypic testing was 100% for amoxicillin and clarithromycin, 97% for levofloxacin, 91% for tetracycline (n = 33), and 67% for metronidazole (n = 24).

Conclusion

WGS provides a detailed analysis of H. pylori resistance and a broader analysis of antimicrobials that may be of clinical value. Additional studies are needed for genotypic prediction of metronidazole resistance.

Disclosures

All authors: No reported disclosures.
2166. Performance Study on the New ETEST® Piperacillin/Tazobactam (P/T) MIC Strip
Authors: Martelin Roland , Pillon Edwige , Cutivet Emilie , Pompilio Marion , Halimi Diane , Durand Geraldine
Published: October 2019

Background

Piperacillin/Tazobactam combination is a first-line antibiotic and carbapenem sparing option for severe infections due to Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii. ETEST® strips allow to determine antimicrobial Minimum Inhibitory Concentration (MIC). ETEST® Piperacillin/Tazobactam (Ptc) was developped in 1995 against agar dilution reference method. Since then, resistance to Piperacillin/Tazobactam has been increasing and broth microdilution (BMD) substituted for agar dilution as the reference method. The new ETEST® P/T strip for determining MIC of Enterobacteriaceae, P. aeruginosa and A. baumannii was developed against BMD using a panel of recent strains well genotypically characterized. The aim of this study was to compare the performance of both strips on a panel of challenging strains harboring different-resistant mechanisms.

Methods

A total of 64 strains were tested using ETEST® P/T, ETEST® PTc and BMD: 48 Enterobacteriaceae including 25 resistant strains and 16 P. aeruginosa including 11 resistant strains. The results were analyzed for essential (EA) and category (CA) agreements, minor (mE), major (ME) and very major (VME) error rates using FDA/CLSI 2019 breakpoints (Enterobacteriaceae, P. aeruginosa: ≤ 16/4(S); ≥ 128/4(R) µg/mL).

Results

Although the panel of strains was challenging including different resistant mechanisms (acquired penicillinase, high-level cephalosporinase, acquired cephalosporinase, ESBL, carbapenemase), the new ETEST® P/T performance was significantly improved for Enterobacteriaceae with an EA at 92,2% without ME or VME. This improvement was also linked to the easiest reading (significant decrease of microcolonies in the ellipse zone). For P. aeruginosa, the performance was similar between the two strips but the new ETEST® P/T was better correlated with the BMD and showed an EA of 100%. The results are summarized in the table.

Conclusion

The new ETEST® P/T improved the MIC determination and resistance detection, as well as the reading of MIC end points for the routine use. This study emphasizes the need to check the performance of the antimicrobial susceptibility testing products by testing strains reflecting the current epidemiology.

Disclosures

All authors: No reported disclosures.
2168. Comparison of Rapid Diagnostic Tests for Bloodstream Infections Using Desirability of Outcome Ranking Management of Antimicrobial Therapy (DOOR-MAT)
Authors: Claeys Kimberly C , Hopkins Teri , Kpadeh-Rogers Zegbeh , Jiang Yunyun , Evans Scott R , Johnson J Kristie , Leekha Surbhi
Published: October 2019

Background

Rapid diagnostic tests (RDTs) for bloodstream infection (BSIs) are increasingly common. Decisions regarding which RDT to implement remains a clinical challenge given the diversity of organisms and resistance mechanisms detected by different platforms. The desirability of Outcome Ranking Management of Antimicrobial Therapy (DOOR-MAT) has been proposed as a framework to compare RDT platforms but reports of clinical application are lacking. This study compared potential antibiotic decisions based on results of two different RDTs for BSI using DOOR-MAT.

Methods

Retrospective study at University of Maryland Medical Center from August 2018 to April 2019 comparing Verigene® BC (VBC) to GenMark Dx ePlex® BCID for clinical blood cultures. VBC was part of standard of care, ePlex was run on discarded fresh or frozen blood samples. In this theoretical analysis, RDT result and local susceptibility data were applied by two Infectious Diseases pharmacists to make decisions regarding antibiotic selection in a blinded manner. Cohen’s Kappa statistic summarized overall agreement. DOOR-MAT, a partial credit scoring system, was applied to decisions based on final organism/susceptibility results (Figure 1). Scores were averaged between reviewers and mean scores compared between RDT systems using the t-test. Additionally, a sensitivity analysis with varied point assignment among Gram-negatives (AmpC-producers) was conducted.

Results

110 clinical isolates were included; 41 Gram-negative, 69 Gram-positive organisms. Overall agreement was 82% for VBC and 83% for ePlex. The average score for VBC was 86.1 (SD 31.3) compared with ePlex 92.9 (SD 22.9), P = 0.004. Among Gram-negatives, the average score for VBC was 79.9 (SD 32.1) compared with ePlex 88.1 (SD 28.8), P = 0.032. Among GPs the average score for VBC was 89.9 (SD 30.4) compared with ePlex 95.8 (SD 18.3), P = 0.048. Sensitivity analysis demonstrated an average score for of 89.9 (SD 30.4) for VBC compared with 95.8 (SD 18.3) for ePlex, P = 0.27.

Conclusion

The use of a partial credit scoring system such as the DOOR-MAT allows for comparisons between RDT systems beyond sensitivity and specificity allowing for enhanced clinical interpretation. In this theoretical comparison, the Genmark ePlex BCID scored higher among both GP and GN organisms.

Disclosures

All authors: No reported disclosures.
2191. The Sputum FilmArray Pneumonia Panel (SFAPP) Outperforms a Diagnostic Bundle in Patients with Community-Acquired Pneumonia (CAP)
Authors: Gilbert David N , White Emma , Ferdosian Shirin , Gelfer Gita , Wang Lian , Leggett James
Published: October 2019

Background

This study compares the detection of respiratory pathogens between a multitest “Bundle” (MTB) and the Sputum FilmArray Pneumonia Panel (SFAPP).

Methods

Patients admitted from the ED with CAP were enrolled. The SFAPP probed for the presence of 18 bacterial species and 17 viral targets. The results were compared with pathogen detection with an MTB: (a) culture of sputum and blood; (b) urine antigens of S. pneumoniae and Legionella pneumophila; (c) Nasopharyngeal (NP) Respiratory FilmArray (NPRFA) panel which detects 17 viruses and 3 bacteria; and (d) nasal NAATs for S. pneumoniae and S. aureus. Two serum procalcitonin (PCT) levels helped separate bacterial colonization from invasion.

Results

Of 400 enrolled patients, 121 (30%) were non-evaluable due to a lack of a sputum specimen, 72 (18%) with a final diagnosis other than CAP, and other reasons in 21 (5%). Herein, the results of 186 (47%) evaluable patients with CAP and the Pneumonia Severity Index values of over 90 in 64.5%. The SFAPP detected viruses in 114/186 (61.3%) patients compared with 73/186 (39.2%) with the NPRFAP, p. The SFAPP detected bacterial pathogen(s) in 140/186 (75.3%) of patients vs. 117/183 (62.9%) with the MTB, pH. influenzae, M. catarrhalis, and S. agalactiae, p. A potential pathogenic bacteria and/or virus was detected in 176 of the 186 (95%) evaluable patients. Patients were classified as: virus detected (22); bacteria detected (57); bacteria and virus (97); CAP but no pathogen detected (10). The distribution of serum PCT levels by pathogen detected is shown in Figure 1. The dashed line is the 0.25 ng/mL “cut-off” to help separate colonization from invasion by bacteria. Antibiotic use was less in influenza patients with low PCT levels, p. In 22 patients with only virus detected and PCT.

Conclusion

The Sputum FilmArray Pneumonia Panel detected more bacteria and viral potential pathogens than the Multitest Bundle that included the Nasopharyngeal FilmArray Panel. The Sputum FilmArray Pneumonia Panel may allow removal of nasopharyngeal swabs and urine antigens from the MTB.

Disclosures

All authors: No reported disclosures.
2199. The Etiology of Community-Acquired Pneumonia with Attention to the Role of Normal Respiratory Flora
Authors: Musher Daniel M , Jesudasen Sirus , Barwatt Joseph W , Cohen Daniel N , Rodriguez-Barradas Maria C
Published: October 2019

Background

Intensive studies have failed to identify an etiologic agent in >50% of patients (patients) who are hospitalized for community-acquired pneumonia (CAP). Gram stain and culture of sputum samples frequently yield “normal respiratory flora” (NRF). We hypothesized that careful study might (1) increase the yield of recognized pathogens; and (2) show, in some patients, an etiologic role for NRF.

Methods

We studied a convenience sample of adults hospitalized for CAP at a VA Medical Center if they met four criteria: (1) clinical syndrome consistent with pneumonia; (2) newly recognized pulmonary infiltrate; (3) sputum with > 10 WBC per epithelial cell; and (4) < 18 hours antibiotic treatment. For quantification of bacteria, sputum was liquefied in 2% N-acetyl cysteine and diluted serially. Other studies in nearly all patients included blood cultures, urine for pneumococcal (Spn) and Legionella antigen, procalcitonin, B-natriuretic protein and PCR for 13 respiratory viruses, Mycoplasma and Chlamydia. >106 bacteria/mL and a consistent Gram stain indicated a bacterial cause, positive viral PCR indicated a viral cause, and both indicated coinfection.

Results

119 patients met study criteria. Recognized bacterial pathogens alone were identified in 47 (40%) cases led by Spn 17 (14%), Haemophilus 17 (14%) and S. aureus 6 (5%). A virus alone was identified in 17 (15%) and coinfection in 11 (9%). We applied these same criteria for NRF. NRF alone were found in 22 (19%) patients with S. mitis predominating. NRF and a respiratory virus were coinfecting in 10 (8%) patients. In total, with the inclusion of NRF, an etiologic agent was found in 95% of patients.

Conclusion

Our high yield is attributable to selection criteria. With a good-quality sputum and absent prolonged antibiotics, a bacterial cause for CAP was found in 59% of patients, a viral cause in 15%, and coinfection in 17%. Bacterial CAP due to recognized pathogen follows microaspiration of colonizing bacteria from the upper airways. Aspiration of a sufficient inoculum of so-called NRF, especially in older adults or those with damaged clearance mechanisms, might well do the same. Careful microbiologic study of patients who are able to provide a valid sputum sample before prolonged antibiotics enables a microbiologic diagnosis in nearly all cases and shows a potential etiologic role for NRF in about 20%.

Disclosures

All authors: No reported disclosures.
2234. Outcomes by Age and Gender from a Global Phase 3 Study of Delafloxacin (DLX) in Community-Acquired Bacterial Pneumonia (CABP)
Authors: Madej Andrzej , Pullman John , Popescu Monica , Quintas Megan , Lawrence Laura , Li Yang , Cammarata Sue
Published: October 2019

Background

Delafloxacin (DLX) is a fluoroquinolone, approved in the United States for treatment of ABSSSI. DLX has no preclinical signals for QT prolongation and has no QT prolongation in a validated challenge study. Risk of QT prolongation is a consideration in antibiotic selection for elderly hospitalized CABP patients. A Phase 3 CABP trial with DLX was analyzed with a focus on age and gender.

Methods

Data on age and gender were reviewed from a multicenter, randomized, double-blind trial of adults with CABP. Patients were randomized 1:1 to DLX or moxifloxacin (MOX) treatment for 5–10 days. Patients received a minimum of 3 days of IV treatment, then were switched to oral at MD discretion. A key clinical endpoint was the investigator-assessment at Test of Cure (TOC) 5–10 days after the end of treatment. Clinical success was defined as complete or near resolution of signs and symptoms and no further antibiotics needed

Results

In the overall study, 859 patients were randomized with a mean age of 60 years (55.5% <65, 44.5% ≥65, 21.2% ≥75; range 18–93); 58.7% were male; 25.4% and 1.4% were PORT class IV and V; 28.6% multi-lobar pneumonia. Table shows the comparison of DLX and MOX clinical response at TOC in the Intent to Treat (ITT) population. Overall, DLX was well tolerated, with similar related adverse events (AE) between treatment groups regardless of age (< 65: 16.7% DLX, 13.3% MOX; ≥ 65: 13.4% DLX, 11.7% MOX) or gender (male: 16.0% DLX, 11.1% MOX; female 14.0% DLX, 14.9% MOX). The most common treatment-related AEs for DLX were diarrhea and transaminase elevations which were mild-to-moderate and did not routinely lead to discontinuation. There were no reports of potential QT prolongation on DLX.

Conclusion

Based on age and gender, DLX had comparable outcomes to MOX in clinical success at TOC. DLX was also well tolerated regardless of age or gender. DLX may offer a promising alternative in the treatment of CABP including elderly patients.

Disclosures

All authors: No reported disclosures.
2236. Stool-Derived Inflammatory Mediators Serve as Biomarkers of Severity in Clostridium difficile Infection
Authors: Motyka Jonathan , Penkevich Aline , Perry D Alex , Weiner Shayna , Standke Alexandra , Keidan Micah , Young Vincent B , Rao Krishna
Published: October 2019

Background

Clostridium difficile infection (CDI) is a major public health concern and frequently results in severe disease, including death. Predicting subsequent complications early in the course can help optimize treatments and improve outcomes. However, models based on clinical criteria alone are not accurate and/or do not validate. We hypothesized that inflammatory mediators from the stool would be biomarkers for severity and complications.

Methods

Subjects were included after testing positive for toxigenic C. difficile by the clinical microbiology laboratory via enzyme immunoassay (EIA) for glutamate dehydrogenase and toxins A/B, with reflex to tcdB gene PCR for discordants. Stool was thawed on ice, diluted 1:1 with PBS and protease inhibitor, centrifuged, and the supernatant was analyzed by a custom antibody-linked bead array with 17 inflammatory mediators. Measurements were normalized and log-transformed. IDSA severity was defined by serum white blood cell count > 15000 cells/µL or creatinine 1.5-fold above baseline. Primary 30-day outcomes were all-cause mortality and attributable disease-related complications (DRC): ICU admission, colectomy, and/or death. Analyses included principal components, permutational multivariate ANOVA (PERMANOVA), and logistic regression ± L1 regularization and 5-fold cross validation. The area under the receiver operator characteristic curve (AuROC) was computed.

Results

We included 225 subjects, with 124 females (55.1%), average age 58.5 (±17), and more PCR+ than toxin EIA+ (170 vs. 55, respectively). IDSA severity, death, and DRCs occurred in 79 (35.1%), 14 (6.2%), and 12 (5.3%) subjects, respectively. PCA and PERMANOVA showed IDSA severity (P = 0.009) but not death or DRCs associated with the panel (figure). Several inflammatory mediators associated with IDSA severity and death (table). Machine learning models had AuROCs of 0.77 (IDSA severity), 0.84 (death), and 0.7 (DRCs).

Conclusion

We found that specific inflammatory mediators from the stool of patients with CDI associate with severity and complications. These results are promising, but need replication in a larger dataset and should be incorporated into models that include clinical covariates prior to deployment.

Disclosures

All authors: No reported disclosures.
2261. Oral Fosfomycin for Treatment of Urinary Tract Infections Due to Extended-Spectrum β-Lactamase and Carbapenem-Resistant Enterobacteriaceae
Authors: Hefler Jade L , Perez Katherine K , Musick William L
Published: October 2019

Background

Urinary tract infections (UTIs) caused by extended spectrum β-lactamase (ESBL) and carbapenem-resistant Enterobacteriaceae (CRE) pose a significant challenge due to limited treatment options. The objective of this study was to compare outcomes in patients treated with standard IV therapy or oral fosfomycin for ESBL and CRE UTIs.

Methods

Retrospective cohort review of inpatients diagnosed with ESBL and CRE UTIs between June 2016 and September 2017 at a seven-hospital system. Patients with polymicrobial UTI, bloodstream infections, additional anatomical site with ESBL/CRE, or those requiring renal replacement therapy were excluded. Only patients with documented fosfomycin susceptible isolates in vitro were included. Eligible patients were divided into two groups: standard IV therapy (SDTx) or fosfomycin therapy (FOS). FOS group could receive ≤72 hours of other active antibiotics from urine culture collection (UTI onset) to the first dose of fosfomycin. Quick sequential organ failure assessment (qSOFA) scores were calculated at UTI onset. The primary endpoint was functional cure defined as resolution of symptoms without microbiological failure. Microbiological failure was defined as a positive urine culture within the index hospitalization or 30 days.

Results

There were 70 patients included: 31 treated with SDTx and 39 with FOS. ESBL Echerichia coli was most common, accounting for 58% of UTIs in SDTx and 71.8% in FOS. ESBLs accounted for 71% (n = 22/31) of UTIs in SDTx and 89.7% (n = 35/39) in FOS. The overall qSOFA score was 0.7 (range, 0–3) with the majority of patients scoring < 2 (80.6% in SDTx vs. 92.3% in FOS; P = 0.29). There was no significant difference in functional cure rate (n = 30, 96.8% SDTx vs. n = 37, 94.9% FOS; P = 0.83). SDTx patients had a longer length of stay (15.3 days vs. 7.3 days with FOS; P = 0.04), duration of active therapy (7.6 days vs. 3 days with FOS; P < 0.0001), and time from UTI onset to discharge (10.3 days vs. 6.6 days with FOS; P = 0.002). There were no adverse drug events reported.

Conclusion

Oral fosfomycin was a safe and effective alternative to standard IV therapy for ESBL and CRE UTIs in this investigation and demonstrated similar functional cure rates. Additionally, patients treated with fosfomycin had shorter hospitalizations and durations of antibiotic therapy.

Disclosures

All authors: No reported disclosures.
2265. Clinical Outcomes with Single vs. Combination Antibiotic Therapy in the Treatment of Burkholderia cepacia complex Bacteremia and Pneumonia
Authors: George G Taylor A , Stevenson Kurt , Balada-Llasat Joan-Miquel , Coe Kelci E
Published: October 2019

Background

Burkholderia cepacia complex (Burkholderia cenocepacia and Burkholderia multivorans) (BCC) are uncommon, yet serious often drug-resistant pathogens of immunocompromised patients, especially in lung transplants; pre-operative infection/colonization is seen as a contraindication to transplant. Optimal treatment for these difficult infections is not known. We examined impact of single vs. combination therapy on patient outcomes.

Methods

All cases of BCC positive pulmonary or blood cultures at The Ohio State University Wexner Medical Center between January 1, 2012 and June 30, 2018 were analyzed. No cystic fibrosis patients were included. All combinations thereof were evaluated. The primary outcomes were 30 all-cause mortality and 30-day infection-related mortality. Secondary outcomes included sterilization of cultures, isolation of a non-susceptible isolate within 30 days of therapy, hospital and intensive care unit (ICU) length of stay, and adverse drug effects (ADE) of therapy including: hyperkalemia, acute kidney injury (AKI), transaminitis, and QTc prolongation.

Results

There were 90 unique patients who grew BCC (22 patients with 92 positive blood cultures; 54 patients with 87 positive pulmonary cultures). Four patients had mixed pulmonary and blood cultures. Ten patients died prior to having treatment for their cultures and were not evaluated. Overall, there were 85 evaluable infection events. Overall 30-day all-cause mortality was 20/85 (23.5%); mortality in blood culture monotherapy 3/14 (21.4%); combination therapy 3/18 (16.7%) (P = 1.00). Mortality in pulmonary culture monotherapy was 6/32 (18.75%); combination 10/30 (33.3%) (P = 0.19). Among blood cultures monotherapy was associated with 8 ADE while combination therapy was 11 (P = 0.82). In pulmonary patients, monotherapy had 16 ADE while combination had 23 (P = 0.03).

Conclusion

Overall mortality trends improved with combination therapy in blood culture patients and with monotherapy patients in pulmonary cultures. These findings are influenced by the limited number of patients available, and the medical co-morbidities of these patients. In lung patients there were significantly fewer ADE associated with monotherapy as opposed to combination therapy.

Disclosures

All authors: No reported disclosures.
2266. Management of Ertapenem-Resistant, Meropenem-Susceptible Enterobacteriaceae
Authors: Srinivas Pavithra , Wu Janet , Neuner Elizabeth A , Pallotta Andrea , Richter Sandra S , Tsigrelis Constantine
Published: October 2019

Background

Carbapenemases are the most frequent mechanism of carbapenem resistance in Enterobacteriaceae. However, alternative mechanisms such as loss of porin channels or up-regulation of efflux pumps can cause intermediate- to high-level resistance to ertapenem (ERTA) and possibly reduced susceptibilities to meropenem (MERO) leading to discordant phenotypic profiles. Clinical implications of discordant carbapenem susceptibilities and optimal therapy options are yet unknown. We sought to describe our experience with carbapenem-discordant Enterobacteriaceae (CDE).

Methods

Descriptive study of hospitalized adult patients with a CDE positive culture from December 1/16 - December 1/18. Discordance was defined as Enterobacteriaceae with an ERTA-resistant and MERO-susceptible phenotype. Primary objective was to describe antibiotic use patterns for CDE infections. Secondary outcomes included infectious diseases (ID) involvement and clinical outcomes. Clinical failure was defined as a composite of in-hospital mortality, switch of definitive therapy due to clinical worsening, re-hospitalization within 30 days for re-infection, or failure to achieve blood culture clearance for ≥7 days.

Results

A total of 55 patients with CDE were identified. Most common organisms were Enterobacter cloacae complex (72%) and Klebsiella pneumoniae (9%). Of 21 isolates tested, 1 (4.8%) was positive for a carbapenemase. Mean age of patients was 61 ± 16 years, 51% were admitted to a medicine service, and 18% were immunocompromised. ID was involved in 82% of CDE cases. Most common sites were urine (33%), wound/tissue (27%), and respiratory (18%). 43/55 (78%) patients were treated – 17/43 (40%) with MERO, 14/43 (33%) with fluoroquinolones. Ceftazidime/avibactam and tigecycline were used in 4 (9%) patients each. Combination therapy was used in 8 (19%) patients, most commonly with MERO or tigecycline. Clinical failure occurred in 21/43 (49%) patients – 8/43 (19%) were receiving MERO-based therapy, 13/43 (30%) were receiving a non-MERO-based therapy.

Conclusion

Discordance between ERTA and MERO susceptibility was more common in Enterobacter spp. Majority of isolates tested negative for a carbapenemase. MERO and fluoroquinolones were the most frequently used antibiotics for treatment of CDE infections.

Disclosures

All authors: No reported disclosures.
2267. Epidemiology of Candida auris Candidemia in a Teaching Hospital in North of Oman: One-Year Survival
Authors: Eatemadi Arash , Al Wahibi Aiman , Al shibli Hilal , Al reesi Ali
Published: October 2019

Background

Recent emergence of Candida auris as a multidrug resistant fungal pathogen, is a serious concerns for public health. However, there is a paucity of reported cases from Oman. Literature search resulted in finding only 7 cases from Oman, reporting C. auris infections in the articles first published in 2017. However, the rate of isolatin is increasing.

Methods

In this study, we included the results of all positive blood cultures of C. auris in Suhar teaching hospital from May 2018 (date of first detection) till end of April 2019. Further confirmation of the species was performed by MALDI-TOF and antibiotic susceptibility test (AST) by Vitek 2 in central public health laboratory (CPHL) of Oman.

Results

We detected 13 patients (9 females, 4 males). The mean age was 58.61% years (28–76 years). All candidemic patients had serious underlying conditions, including prolonged hospital stay or extensive and prolonged antimicrobial exposure or medical comorbidities (8 of 13). The time from hospital admission to onset of C. auris candidemia was 8–49 days, with a median of approximately 27 days. The most common isolated co- pathogen from blood culture was K. pneumonia (without regard to Coagulase-negative staphylococci). As average, every patient received 4.8 kind of different antibiotics in mean 88 doses before candidemia developed and piperacillin–tazobactam was the most common used antibiotics. AST was done just for 5 patients and revealed high-level resistance to fluconazole and Amphotricin B while, Echinocandins (anidulafungin, caspofungin) were fully sensitive and voricunazole had intermediate sensitivity. Mean duration of anti-fungal treatment was 12.5 days (5 – 26 days). 8 patients treated by Echinocandins (4/8 died), 4 by Fluconazole (3/4 died) and one without treatment discharged. 30-day all-cause mortality was 61.5%.

Conclusion

In Oman, C. auris has been reported from many hospitals. Resistance to several antifungal agents and persistence in the hospital environment make this organism a potential menace for the treating physician and the infection control personnel. In our hospital, every candidemic patient should be treated with Echinocandins and assumed to be resistant to Fluconazole until proven otherwise according to results of AST.

Disclosures

All authors: No reported disclosures.
2286. Evaluating the Impact of Ceftolozane/Tazobactam on Clinical Outcomes in Patients with Multi-Drug-resistant Pseudomonas aeruginosa Pneumonia
Authors: Mills Matthew , MacWhinnie Ashley , Do Timmy
Published: October 2019

Background

Ceftolozane/tazobactam is a novel cephalosporin and β-lactamase inhibitor antibiotic that has shown to have potent activity against Pseudomonas aeruginosa including strains exhibiting multi-drug resistance (MDR). The purpose of this study was to evaluate ceftolozane/tazobactam efficacy in MDR P. aeruginosa pneumonia compared with historical standard of care.

Methods

This was a retrospective cohort study of patients hospitalized across AdventHealth Central Florida campuses with MDR P. aeruginosa pneumonia from January 1, 2017 through December 31, 2018. This study included patients ≥ 18 years of age with a diagnosis of pneumonia and a positive respiratory culture with MDR P. aeruginosa. The primary outcome of this study was the rate of clinical cure by day 14 of definitive therapy. Secondary outcomes included 30-day readmission rate, average hospital length of stay (LOS), cost of admission, average ICU LOS after initiation of definitive antibiotic, and total days of antibiotic exposure for pneumonia. Data were analyzed with statistical computer software utilizing independent samples t-test and chi square tests of independence as appropriate.

Results

A total of 115 patients were included in the final analysis, 62 patients treated with ceftolozane/tazobactam and 53 patients treated with historical standard of care. Rate of clinical cure was similar between patients treated with ceftolozane/tazobactam, 72.6% (n = 45), and those treated with historical standard of care, 67.9% (n = 36), {X2 (1) = 0.297, p = 0.683}. Other outcomes assessed were also similar between groups except for average hospital length of stay (42.7 days vs. 30.3 days t(113) = 2.054, p = 0.042), and cost of admission ($78,550 vs. $47,681, t(113) = 2.458, p = 0.016), which were significantly greater in the ceftolozane/tazobactam treatment group.

Conclusion

In patients diagnosed with MDR P. aeruginosa pneumonia, clinical cure rates were not significantly different between those treated with ceftolozane/tazobactam compared with historical standard of care. Significantly greater hospital length of stay and cost of admission was associated with use of ceftolozane/tazobactam, although many patient factors may have influenced these results.

Disclosures

All authors: No reported disclosures.
2289. Bacterial Causes of Acute Bacterial Skin and Skin Structure Infections (ABSSSI) in Patients with Intravenous Drug Use (IVDU): Phase 3 REVIVE Studies
Authors: Huang David B , Noviello Stephanie S , Balser Barbara , Scaramucci Amy E , Desplats Eve , Corey G R
Published: October 2019

Background

Opioid addiction in the United States has reached epidemic proportions threatening public health. This analysis evaluates the baseline characteristics and bacterial causes of ABSSSI in patients who were IVDU from two parallel Phase 3 trials comparing the treatment of iclaprim with vancomycin.

Methods

A total of 621 patients who were IVDU from two parallel Phase 3, double-blind, randomized (1:1), active-controlled, multinational, multicenter trials (REVIVE-1 and REVIVE-2) were analyzed both separately and pooled. This post-hoc analysis summarizes the baseline bacterial causes of ABSSSI identified among IVDU. Per protocol, ABSSSI (major abscesses, cellulitis, or wound infections) were defined as having either the presence of purulent or seropurulent drainage before or after surgical intervention of the wound or at least 3 of the following signs and symptoms: discharge, erythema (extending at least 2 cm beyond the wound edge in any direction), swelling and/or induration, heat and/or localized warmth, and/or pain and/or tenderness to palpation. IVDU was defined based on subjected-reported medical history. At the baseline visit, ABSSSI were sampled for microbiological culture. Cultures were performed locally, and isolates were submitted to the central microbiology laboratory.

Results

Among IVDU with ABSSSI, average age was 44 years, 67.6% were male, average lesion size was 322 cm2, 10.8% had abnormal renal function (CrCl ≤ 90 mL/minute), and 3.9% had bacteremia. The bacterial causes of ABSSSI among IVDU are shown in the Table.

Conclusion

IVDU, a growing population, are vulnerable to ABSSSI. S. aureus, including MRSA, and S. anginosus group were the most commonly identified bacterial causes of ABSSSI in patients who are IVDU. Therefore, antibiotic selection should cover these bacteria among IVDU who present with an ABSSSI.

Disclosures

All authors: No reported disclosures.
2294. Comparative Evaluation of Ertapenem and Clindamycin Plus Gentamicin for the Treatment of Postpartum Endometritis
Authors: Schweiger Krislyn , Donaghy Henry , Meirowitz Natalie , Ahn Seunjun , Doan Thien-Ly
Published: October 2019

Background

Clindamycin plus gentamicin (C/G) is the most commonly used regimen for the treatment of postpartum endometritis. With a similar spectrum of coverage and once daily dosing, ertapenem is an attractive alternative. The purpose of this study was to evaluate the efficacy of ertapenem compared with C/G, for the treatment of postpartum endometritis.

Methods

This was a retrospective chart review (IRB-approved) of patients treated with either ertapenem or C/G for endometritis, from July 2017 to July 2018. Patients receiving agents from both groups were excluded. Data collected included: demographics, ante- and intrapartum course, including efficacy parameters and antimicrobial use. Secondary objectives included a safety outcomes and patient quality analysis. Appropriate statistical analysis was performed.

Results

A total of 81 patients were included (40 in C/G arm, 41 in ertapenem arm). No differences in mean length of stay (5.98 vs. 5.61 days in C/G and ertapenem, P = 0.61), readmission within 14 days, or mortality were seen. No patients developed acute kidney injury, C. difficile infection, or ototoxicity. All patients in the ertapenem arm had appropriate dosing, compared with 27.5% in C/G arm (P < 0.0001). Inappropriate dosing in 79% of C/G group was attributed to under-dosing of gentamicin. For quality measures, patients in C/G arm had more nighttime interruptions (3 vs. 1 interruptions per patient). 46% of patient in the ertapenem group had no overnight interruptions compared with 0% in C/G group. There were 2 suspected wound infections in the C/G group, but none in ertapenem group.

Conclusion

No difference in efficacy was seen between ertapenem and C/G for treatment of postpartum endometritis Ertapenem was associated with less inappropriate dosing and fewer nighttime interruptions Improvement in patient experience and reduction of nursing workload may outweigh the small additional cost of ertapenem.

Disclosures

All authors: No reported disclosures.