bluuebunny/crossref_metadata_2025_split huggingface dataset:
1587. Activity of Ceftolozane/Tazobactam against Gram-Negative Isolates from Lower Respiratory Tract Infections – SMART United States 2018
Authors: Lob Sibylle , Hackel Meredith , DePestel Daryl , Young Katherine , Motyl Mary , Sahm Daniel F 
Published: January 2021

Abstract

Background
Ceftolozane/tazobactam (C/T) is an antipseudomonal cephalosporin combined with a β-lactamase inhibitor. C/T has been approved by the FDA and EMA for complicated urinary tract infections, complicated intraabdominal infections, and hospital-acquired and ventilator-associated bacterial pneumonia. Using isolates collected in the United States as part of the global SMART surveillance program, we evaluated the activity of C/T and comparators against gram-negative pathogens collected from patients with lower respiratory tract infections (LRTI).

Methods
In 2018, 24 hospitals in the US each collected up to 100 consecutive aerobic or facultative gram-negative bacilli (GNB) from LRTI for a total of 1773 isolates. MICs were determined using CLSI broth microdilution and breakpoints. C/T-nonsusceptible (NS) Enterobacterales and P. aeruginosa isolates were screened by PCR and sequencing for genes encoding β-lactamases.

Results
The 3 most common species collected from LRTI were P. aeruginosa (35.0% of all collected GNB), K. pneumoniae (10.4%), and E. coli (9.6%). Enterobacterales and P. aeruginosa combined comprised 86.3% of all collected LRTI GNB. The activity of C/T and comparators against GNB from LRTI is shown in the table.
C/T was active against 93% of Enterobacterales isolates from LRTI (activity only exceeded by meropenem and amikacin), as well as against 97% of P. aeruginosa and 94% of all Enterobacterales and P. aeruginosa combined (activity only exceeded by amikacin). C/T maintained activity against 69-83% of β-lactam-NS subsets of Enterobacterales and P. aeruginosa combined.
Among 67 molecularly characterized C/T-NS Enterobacterales isolates, 19.4% carried KPC, 1.5% acquired AmpC, and 16.4% only extended-spectrum β-lactamases. No acquired β-lactamases were detected in the remaining 62.7% of isolates, of which 92.9% were species with intrinsic AmpC. Among 21 molecularly characterized C/T-NS P. aeruginosa, one isolate carried an IMP-type metallo-β-lactamase, and in the remaining isolates no acquired β-lactamases were detected.
Table

Conclusion
With its broad coverage of Enterobacterales and P. aeruginosa, C/T can provide an important empiric therapy option for patients with LRTI in the US.

Disclosures
Sibylle Lob, PhD, IHMA (Employee)Pfizer, Inc. (Consultant) Daryl DePestel, PharmD, BCPS-ID, Merck & Co, Inc (Employee) Katherine Young, MS, Merck & Co., Inc. (Employee, Shareholder)Merck & Co., Inc. (Employee, Shareholder) Mary Motyl, PhD, Merck & Co, Inc (Employee, Shareholder) Daniel F. Sahm, PhD, IHMA (Employee)Pfizer, Inc. (Consultant)Shionogi & Co., Ltd. (Independent Contractor)
1592. Antimicrobial Activity of Ceftazidime-Avibactam and Comparator Agents Against Enterobacterales and Pseudomonas aeruginosa With Overexpression of AmpC β-Lactamase From Phase 3 Clinical Trials
Authors: Lin Lynn-Yao , Debabov Dmitri , Chang William , Rappo Urania 
Published: January 2021

Abstract

Background
AmpC overproduction is a main mechanism of carbapenem resistance, in the absence of acquired carbapenemases. Ceftazidime-avibactam (CAZ-AVI) has potent in vitro activity against AmpC-producing P. aeruginosa and Enterobacterales that are resistant to carbapenems and other β-lactams.

Methods
Activity of CAZ-AVI and comparators was evaluated against AmpC-overproducing Enterobacterales (n=77) and P. aeruginosa (n=53) collected from 4 CAZ-AVI clinical trials: RECLAIM (complicated intra-abdominal infection [cIAI]), REPRISE (cIAI/complicated urinary tract infection [cUTI]), RECAPTURE (cUTI) and REPROVE (hospital-acquired pneumonia/ventilator associated pneumonia). In vitro susceptibility of CAZ-AVI and comparators was performed by broth microdilution using ThermoFisher custom panels. CLSI breakpoints were used to determine susceptibility. Quantitative PCR and microarray data were used to characterize presence and expression of AmpC. Clinical response at test of cure was assessed.

Results
Against 77 AmpC-overproducing Enterobacterales isolates, meropenem-vaborbactam (MVB) (98.7% susceptible [S]), CAZ-AVI (96.1% S), and meropenem (MEM) (96.1% S) had similar in vitro activity (Table), with greater in vitro activity than amikacin (AMK) (84.4% S), gentamicin (61.0% S), and ceftolozane-tazobactam (TZC) (35.1% S). Clinical cures in patients with baseline AmpC-overproducing Enterobacterales were 21/26 (81%) in CAZ-AVI group vs 17/20 (85%) in control groups. Against 53 AmpC-overproducing P. aeruginosa isolates, CAZ-AVI (73.6% S) showed greater in vitro activity than AMK (69.8% S), TZC (58.5% S), and MEM (37.7% S). Clinical cures in patients with baseline AmpC-overproducing P. aeruginosa were 12/14 (86%) in CAZ-AVI group vs 9/12 (75%) in control groups. MIC distributions against the same P aeruginosa isolates were CAZ-AVI (MIC50/90, 4/ &gt;64 µg/mL), MVB (MIC50/90, 8/32 µg/mL), and MEM (MIC50/90, 8/32 µg/mL).
Table

Conclusion
CAZ-AVI was the most active agent against AmpC-overproducing P. aeruginosa with higher proportion of clinical cure than controls. CAZ-AVI was also among the most active agents against AmpC-overproducing Enterobacterales, with &gt;96% isolates susceptible.

Disclosures
Lynn-Yao Lin, MS, AbbVie (Employee) Dmitri Debabov, PhD, AbbVie (Employee) William Chang, BS, AbbVie (Employee) Urania Rappo, MD, MS, PharmD, Allergan (before its acquisition by AbbVie) (Employee)
1597. Ceftolozane-Tazobactam and Meropenem Synergy Testing Against Multi-Drug and Extensively-Drug Resistant Pseudomonas aeruginosa
Authors: Chua Mary Francine P , Nida Syeda Sara , Lawhorn Jerry , Koirala Janak 
Published: January 2021

Abstract

Background
Multidrug-resistant (MDR) and extensively drug-resistant (XDR) Pseudomonas aeruginosa (PA) have limited therapeutic options for treatment. Ceftolozane/tazobactam is a newer anti-pseudomonal drug effective against resistant PA infections, however resistance against this drug has now also developed and is increasing. In this study, we explored the combination of ceftolozane/tazobactam (CT) and meropenem (MP) as a possible effective regimen against MDR and XDR PA.

Methods
We obtained 33 non-duplicate isolates of MDR and XDR PA grown from blood, urine and respiratory samples collected from patients admitted between 2015 and 2019 at our two affiliate teaching hospitals. MDR PA was defined as resistance to 3 or more classes of anti-pseudomonal antibiotics, and XDR PA as resistance to all but two or less classes of anti-pseudomonal antibiotics. Antimicrobial preparations of both MP and CT were made according to manufacturer instructions. Susceptibility testing was performed using the checkerboard method in accordance to CLSI guidelines (CLSI M100, 2017). The ATCC 27853 strain of PA used as control. Synergy, additive effect, indifference and antagonism were defined as FIC (fractional inhibitory concentration) indices of ≤0.5, &gt;0.5 to &lt;1, &gt;1 to &lt;4, and &gt;4, respectively.

Results
Thirteen (39%) of 33 PA isolates were classified as XDR, while 20 (61%) PA isolates were MDR. All isolates were resistant to MP (MIC50 &gt;32 ug/mL), while only 2 (6%) isolates were susceptible to CT (MIC50 64 ug/mL). A synergistic effect was seen in 9 (27.3%) of PA isolates (FIC index range 0.28 to 0.5)— 2 of which were XDR PA, and 7 were MDR PA. An additive effect was seen in 12 (36.4%), with indifference seen in 12 (36.4%) of isolates. In this study, no antagonism was seen when CT and MP were combined.

Conclusion
When used in combination, CT and MP can exert a synergistic effect against MDR and XDR PA. Additive effect and indifference can also be seen when both antibiotics were used. Moreover, there was no antagonism seen when both antibiotics were combined. This study shows that the use of CT and MP in combination may be an option against XDR and MDR PA infections.

Disclosures
All Authors: No reported disclosures
1600. Closing the gap on moxifloxacin breakpoints for Stenotrophomonas maltophilia
Authors: Stone Tyler J , Summers Kate , Williamson John , Palavecino Elizabeth , Palavecino Elizabeth 
Published: January 2021

Abstract

Background
Moxifloxacin (MOX) has in vitro activity against Enterobacterales and Stenotrophomonas maltophilia (SM). Although MOX commonly displays lower minimum inhibitory concentration (MIC)50/90 values against SM when compared to levofloxacin, there are currently no established MOX breakpoints for treatment of SM. The Clinical and Laboratory Standards Institute (CLSI) has established interpretive categories and MIC breakpoints for levofloxacin (S ≤2µg/ml) against SM. The US Food and Drug Administration and European Committee on Antimicrobial Susceptibility Testing provide MOX breakpoints for Enterobacterales with susceptible MICs represented at ≤ 2 µg/mL and ≤ 0.25 µg/mL, respectively. The purpose of this study was to evaluate MOX MIC distribution against SM strains recovered from clinical specimens.

Methods
Clinical samples from patients with suspected infection during calendar year 2018 and 2019 were processed in the microbiology lab of Wake Forest Baptist Medical Center. After incubation, SM colonies were identified by MALDI-TOF system. MOX susceptibility testing was performed for these clinical isolates by gradient diffusion strip methodologies. Results were displayed as MIC (µg/mL) without interpretation. MIC50/90 and susceptibility rates at potential breakpoints were calculated.

Results
A total of 211 isolates were tested, 112 from 2018 and 99 from 2019. MOX MIC50 and MIC90 for all isolates was 0.25 µg/mL and 2 µg/mL, respectively. The range of MIC distribution was ≤ 0.006 µg/mL to ≥ 64 µg/mL. Percent susceptibilities at incremental MICs, including established MOX breakpoints against Enterobacterales and established levofloxacin breakpoints against SM, are represented in Table 1. MIC distribution was plotted in Figure 1.
Table 1. Susceptibility rates of S. maltophilia to moxifloxacin at theoretical breakpoints

Figure 1. Moxifloxacin MIC Distribution against All S. maltophilia Isolates

Conclusion
With no established breakpoint, these data represent one of the largest samples of MOX MICs against SM in the United States. Using the CLSI breakpoint for levofloxacin in SM (MIC of ≤2ug/ml) the overall susceptibility rate is 93%. This finding highlights the importance of performing susceptibility testing to this agent by the microbiology laboratory and the critical need for MOX breakpoints in SM.

Disclosures
Tyler J. Stone, PharmD, Paratek (Research Grant or Support) John Williamson, PharmD, Paratek (Research Grant or Support) Elizabeth Palavecino, MD, Paratek (Grant/Research Support)Paratek (Grant/Research Support)
1601. Combination Therapy versus Monotherapy for Carbapenem-resistant Organisms: Is More Really Better?
Authors: Najia Laila , Carr Amy , Alexander Jose , Minor Sarah B 
Published: January 2021

Abstract

Background
Carbapenem-resistant organisms (CROs) represent an urgent public health threat and associated with mortality rates up to 60%. Pharmacotherapy for these infections remain challenging and historically included multiple agents. Meropenem/vaborbactam and ceftazidime/avibactam are options to treat CRO infections as monotherapy; however, combination therapy is still frequently utilized. Data evaluating outcomes of patients who received combination therapy compared to those receiving monotherapy for CRO infections is limited.

Methods
This retrospective analysis was completed across 7 campuses at AdventHealth Orlando (AHO) from March 2018-October 2019. AHO implemented CRO PCR testing in March 2018, to identify carbapenemase producing CROs (CP-CROs). Inclusion criteria were hospitalization, age ≥ 18 years, culture with CP-CRO detected by PCR, and ≥ 72 hours of either monotherapy or combination therapy. Primary outcome was clinical success, defined as resolution of signs and symptoms of infection and absence of recurrent infection. Secondary outcomes included mean length of therapy, mean length of stay, inpatient mortality, adverse reactions and 30-day all cause readmissions.

Results
CRO was isolated 68 times in 59 unique patients (56% male, mean age 62 years). Most common sources included urine (41%), sputum (24%) and wound (22%). Commonly isolated organisms include K. pneumoniae (44%) and E. cloacae (29%). Thirty infections (44%) were polymicrobial and 28 patients (41%) had a secondary source of infection. Forty-three patients (63%) received definitive treatment therapy with a single antibiotic. Monotherapy treated patients had higher rates of treatment success (79% vs 68%, p=0.39), lower in-hospital mortality (4% vs 9%, p=0.066), less nephrotoxicity (6% vs 10%, p=0.084), shorter length of therapy (9.6 vs 13.4 days, p=0.034) and shorter hospital stay (20 vs 34 days, p=0.056). All-cause readmission rates were higher in the monotherapy group (18% vs 9%, p=0.78). Minimum inhibitory concentrations (MIC) were reported in 97% of patients.

Conclusion
Treatment with a single antibiotic for carbapenem-resistant infections can lead to treatment success, while minimizing adverse events, compared to utilizing combination therapy.

Disclosures
All Authors: No reported disclosures
1604. Cost-Effectiveness of Ceftazidime-Avibactam for Patients with Hospital-Acquired Pneumonia Caused by Multi-Drug Resistant Enterobacteriaceae or Pseudomonas in China
Authors: Furnback Wesley , Chen YiXi , Dong Peng , Wang Bruce , Ansari Wajeeha , Charbonneau Claudie , Dong Hengjing 
Published: January 2021

Abstract

Background
To estimate the cost-effectiveness of ceftazidime-avibactam (CAZ-AVI) for the treatment of hospital-acquired pneumonia (HAP) including ventilator-associated pneumonia (VAP) caused by multi-drug resistant enterobacteriaceae (MDRE) or MDR pseudomonas aeruginosa (MDRPA) in China.

Methods
A previously published patient-level simulation model was localized to China to estimate the cost-effectiveness of first-line CAZ-AVI compared to meropenem from a healthcare perspective. Patients flowed through the model which evaluates resistance status, response, and adverse events (AEs), which can all lead to a treatment switch. Second-line therapy of colistin plus high dose meropenem was used for both arms. Resistance rates were 0.7% (CAZ-AVI) and 7.6% (meropenem) for MDRE, and 10.7% (CAZ-AVI) and 35.5% (meropenem) for MDRPA. Effectiveness rates for CAZ-AVI and meropenem were based on a randomized, double-blind, phase 3 clinical trial. All cost data, including drugs, AEs, and hospitalization were localized to China. Utility values were based on response and sourced from the literature. Costs and benefits were discounted at 5% over the five year time horizon.

Results
At a cost-effectiveness threshold of three-times GDP per capita, CAZ-AVI was cost-effective compared to meropenem for HAP/VAP caused by both MDRE and MDRPA with ICERs of ¥147,500 and ¥30,496, respectively. Specifically, CAZ-AVI had ¥13,699 and 0.09 additional total costs and QALYs, respectively, within MDRE; ¥5,207 and 0.17 additional total costs and QALYs, respectively, within MDRPA. Length of stay was reduced by 0.65 days and 1.37 in the CAZ-AVI arms of the MDRE and MDRPA analyses, respectively.

Conclusion
CAZ-AVI is a cost-effective alternative to meropenem in the treatment of HAP/VAP caused by MDRE or MDRPA in China.

Disclosures
Wesley Furnback, BA, Pfizer (Consultant) YiXi Chen, MSc, Pfizer (Employee) Peng Dong, PhD, Pfizer (Employee) Bruce Wang, PhD, Pfizer (Consultant) Wajeeha Ansari, MSc, Pfizer (Employee) Claudie Charbonneau, PhD, Pfizer (Employee) Hengjing Dong, MD, Pfizer (Other Financial or Material Support, Honorarium)
1607. Dual Therapy with Aztreonam & Ceftazidime/Avibactam Against Multi-Drug Resistant Stenotrophomonas maltophilia on Tricuspid Valve Endocarditis
Authors: Alexander Jose , Carr Amy , Minor Sarah B , Navas Daniel 
Published: January 2021

Abstract

Background
Antimicrobial resistance in Stenotrophomonas maltophilia is one of the most complex among Gram-negatives. Presence of regulating non-specific antimicrobial class efflux pumps and chromosomal encoded L1 metallo-betalactamase (Ambler Class B) and L2 betalactamase (Ambler Class A) are responsible for few clinically active antimicrobials and pan-drug resistant strains.

Methods
A 38 year old male with a history of IV drug use, chronic hepatitis C, and recent MSSA endocarditis was admitted with sepsis. Workup revealed tricuspid valve endocarditis with pulmonary septic emboli due to S. maltophilia. Initial antibiotics were levofloxacin (LVX), metronidazole, and piperacillin-tazobactam (TZP) followed by LVX and minocycline (MIN). He had valve replacement on day 6. Repeat blood cultures and valve tissue culture revealed pan-resistant S. maltophilia (resistant: ceftazidime (CAZ), LVX, MIN, TMP/SMX, chloramphenicol; intermediate: MIN; eravacycline MIC 8 μg/mL; tigecycline MIC 16 μg/mL). Microbiology Department was consulted for additional antimicrobial options. In vitro testing for aztreonam (ATM) with ceftazidime/avibactam (CZA) was recommended.

Results
Synergy testing between ATM and CZA was performed by positioning ATM strip over the area where CZA had been previously been placed and removed after 10 minutes of incubation. The interception of the growth with the ATM strip was read. In presence of avibactam, ATM MIC was 4 μg/mL, 6 two-fold dilutions lower than ATM without CZA. MIC for ATM (256 μg/mL), CAZ (256 μg/mL) and CZA (32 μg/mL) were tested individually. ATM with CZA was recommended as a salvage treatment based on in vitro result. Patient completed 6 weeks of ATM with CZA along with MIN. He achieved microbiologic clearance and clinical recovery from infection. At the end of treatment, he experienced episodes of refractory ascites. With complex comorbidities, patient was not a transplant candidate and transitioned to hospice two weeks later.

Conclusion
Although the surgical excision was key, treatment with ATM and CZA provided effective antimicrobial treatment in the setting of persistent positive blood culture. ATM with CZA should be considered for cases of pan-drug resistant S. maltophilia with limited treatment options.

Disclosures
All Authors: No reported disclosures
1608. Efficacy of Ceftolozane/Tazobactam for Multidrug-Resistant Gram-Negative Infections in Multiple Urban Hospitals
Authors: Cabrera Nicolo , Tran Truc T , Carlson Travis J , Alnezary Faris , Miller William R , Dinh An Q , Hanson Blake , Munita Jose , Shelburne Samuel A , Aitken Samuel L , Aitken Samuel L , Garey Kevin W , Garey Kevin W , Puzniak Laura A , Arias Cesar A 
Published: January 2021

Abstract

Background
Ceftolozane/tazobactam (C/T) is a novel cephalosporin/beta-lactamase inhibitor combination developed for use against multidrug-resistant (MDR) Gram-negative infections, particularly Pseudomonas aeruginosa (PA). C/T is approved for complicated urinary tract and intraabdominal infections as well as hospital-acquired/ventilator-associated bacterial pneumonias. However, comprehensive clinical characterization of patients treated with C/T in non-FDA-approved indications is limited.

Methods
Patients ≥18 years who received C/T for ≥48 hours while hospitalized in 9 acute care centers in Houston, TX from January 2016 through September 2018 were included. Demographic, microbiologic, treatment and clinical outcome data were retrospectively collected by chart review. In patients who received multiple inpatient courses of C/T, only the first course with C/T was assessed.

Results
210 patients met inclusion criteria: 58% were non-white, 35% were female and 13% were immunocompromised. Median age was 61 years (IQR, 48 to 69). Median Charlson comorbidity index was 5 (IQR, 2 to 6). At the onset of the index episode, a significant proportion of patients required intensive care unit admission (44%), mechanical ventilation (37%) and pressor support (22%). Respiratory sources were the most common (50%) followed by urine (15%). Positive cultures were documented in 93% of the cases and PA was found in 86%. Majority (95%) of PA which were MDR. C/T use was guided by susceptibility testing of the index isolate in ca. 52%. In 5.7% of cases, C/T was used to escalate therapy without any documented C/T-susceptible organism. Half (51%) of the cohort received initial dosing appropriate for renal function while 36% receiving a lower than recommended dose. Clinical success (i.e., recovery from infection-related signs and symptoms) occured in 77%. The in-hospital mortality rate in our cohort was 15% with 26 of 31 deaths deemed infection-related.

Conclusion
We report a large multicenter observational cohort that received C/T. A 77% clinical success with the use of C/T was documented. These data support the use of C/T in critically ill patients infected with MDR PA.

Disclosures
William R. Miller, MD, Entasis Therapeutics (Scientific Research Study Investigator)Merck (Grant/Research Support)Shionogi (Advisor or Review Panel member) Laura A. Puzniak, PhD, Merck (Employee) Cesar A. Arias, MD, MSc, PhD, FIDSA, Entasis Therapeutics (Scientific Research Study Investigator)MeMed (Scientific Research Study Investigator)Merck (Grant/Research Support)
1609. Epidemiology and Susceptibility to Imipenem/Relebactam of Gram-Negative Pathogens from Patients with Lower Respiratory Tract Infections – SMART United States 2017-2018
Authors: Lob Sibylle , Hackel Meredith , Young Katherine , Motyl Mary , Sahm Daniel F 
Published: January 2021

Abstract

Background
Relebactam (REL) inhibits class A and C β-lactamases and was approved in the US combined with imipenem (IMI) and cilastatin for complicated urinary tract and intraabdominal infections. Using isolates collected as part of the global SMART surveillance program in the US, we evaluated the activity of IMI/REL against gram-negative pathogens (GNP) from patients with lower respiratory tract infections (LRTI), including a comparison of isolates from ICU and non-ICU wards.

Methods
In 2017-2018, 27 US hospitals each collected up to 100 consecutive aerobic or facultative GNP from LRTI patients per year. MICs were determined using CLSI broth microdilution and breakpoints.

Results
Among 3878 GNP isolates from LRTI, the most common species collected were P. aeruginosa (Psa, 33.3%), K. pneumoniae (10.9%), E. coli (10.4%), and S. marcescens (6.9%). Susceptibility of GNP is shown in the table.
IMI/REL inhibited 93% of Psa and Enterobacterales, which included 174 isolates of Morganellaceae that are not expected to be susceptible to IMI or IMI/REL. S. marcescens also showed low susceptibility to IMI, with improved but still reduced activity upon addition of REL. IMI/REL inhibited 83% of all GNP combined, 7-18 percentage points higher than the comparator β-lactams. Of the tested comparators, only amikacin exceeded the activity of IMI/REL.
Only Psa showed substantial differences in susceptibility between isolates from ICU (n=486) and non-ICU wards (n=611), with 63.4% and 70.2%, respectively, susceptible to IMI, 71.6/78.7% to cefepime, and 64.2/73.3% to piperacillin/tazobactam (P/T). Susceptibility to IMI/REL was high in both settings (91.4/93.6%). Among Enterobacterales, susceptibility was generally similar in ICU and non-ICU wards (IMI/REL, 92.5% in both settings; IMI, 86.3 and 87.1%, respectively; cefepime, 89.9/89.0%; P/T, 88.7/87.4%).
Table

Conclusion
Although resistance rates have frequently been reported to be higher in ICU than non-ICU wards, this pattern was seen in the current study only among Psa isolates. IMI/REL showed activity &gt;90% against both Enterobacterales and Psa from both ward types. These in vitro data suggest that IMI/REL could provide an important treatment option for patients with LRTI in the US, including those in ICUs.

Disclosures
Sibylle Lob, PhD, IHMA (Employee)Pfizer, Inc. (Consultant) Katherine Young, MS, Merck & Co., Inc. (Employee, Shareholder)Merck & Co., Inc. (Employee, Shareholder) Mary Motyl, PhD, Merck & Co, Inc (Employee, Shareholder) Daniel F. Sahm, PhD, IHMA (Employee)Pfizer, Inc. (Consultant)Shionogi & Co., Ltd. (Independent Contractor)