bluuebunny/crossref_metadata_2025_split huggingface dataset:
1228. Outcomes Associated with Empiric Cefepime or Meropenem for Bloodstream Infections Caused by Ceftriaxone-Resistant, Cefepime-Susceptible Escherichia coli and Klebsiella pneumoniae
Authors: Frescas Brian E , McCoy Christopher , Kirby James , Bowden Robert , Mercuro Nicholas J 
Published: December 2021

Abstract

Background
Cefepime is a 4th generation cephalosporin frequently used for empiric sepsis therapy. Dose- and MIC-dependent efficacy of cefepime is supported by the Clinical & Laboratory Standards Institute, however its use in infections due to extended-spectrum beta-lactamase-producing Enterobacterales is controversial. This study aims to compare outcomes in patients given empiric meropenem or cefepime for bloodstream infections (BSI) caused by ceftriaxone-resistant E. coli and K. pneumoniae.

Methods
This single-center retrospective cohort included adults hospitalized from 2010 - 2020 and received empiric cefepime or meropenem for BSI caused by ceftriaxone-resistant E. coli or K. pneumoniae. In the cefepime group, only organisms with MIC ≤ 2 mg/L were included. Patients who received the empiric agent for &lt; 48 hours, or received an additional active agent within 48 hours were excluded. The primary outcome was 30-day mortality; secondary outcomes were recurrent infection, readmission, and time to clinical stability. Chi-squared or Fisher’s exact was used for categorical variables and Mann-Whitney-U for continuous variables. Inverse probability treatment weighing was used to determine the impact of empirical therapy on clinical stability at 48 hours.

Results
Fifty-four patients were included: 36 received empiric meropenem, 18 received cefepime. There were no significant differences in baseline severity of illness or comorbid conditions. Urinary source was less common in the meropenem group compared to cefepime (52.8 vs 83.8%, p=0.028) (Table 1). There was no difference in 30-day mortality between meropenem and cefepime (2.8 vs 11.1%, p = 0.255). More patients achieved clinical stability at 48 hours on empiric meropenem compared to cefepime (75 vs 44.4%, p = 0.027), and time to clinical stability was significantly shorter (median 21.3 vs 38.5 hours, p = 0.016). Most patients in the meropenem and cefepime groups completed definitive treatment with a carbapenem (88.9 vs 72.2%, p=0.142).
Table 1: Results

Summary of primary and secondary outcomes

Conclusion
There was no difference in mortality between patients receiving empiric cefepime for BSI due to ceftriaxone-resistant Enterobacterales, with cefepime MIC ≤ 2 mg/L, compared to meropenem; however, time to clinical stability was significantly delayed.

Disclosures
James Kirby, MD, D(ABMM), First Light Biosciences (Board Member)TECAN, Inc. (Research Grant or Support)
1230. Evaluation of the Interplay Between β-lactamases and Porin Production on β-Lactam MICs in Klebsiella pneumoniae
Authors: Whitney Alyssa K , Hanson Nancy D 
Published: December 2021

Abstract

Background
K. pneumoniae can emerge resistant to β-lactam antibiotics through the production of β-lactamase enzymes and/or loss of the outer membrane porins, OmpK35, OmpK36, and/or PhoE. While both mechanisms are hypothesized to work synergistically, β-lactamases have been the focus of previous studies. As a result, the contribution of outer membrane porin loss to the β-lactam minimum inhibitory concentration (MIC) is unknown. The objective of this study was to evaluate the contribution of specific β-lactamases and porin production to β-lactam susceptibility. We hypothesize that production of a β-lactamase in a clinical isolate deficient in 3 major porins will result in higher β-lactam MICs but not always a resistant phenotype.

Methods
The structural gene and promoter of CTX-M-14, CTX-M-15, and CMY-2 were cloned into a low copy number vector and transformed into Kp 23, a wild-type clinical isolate, and KPM 20, a clinical isolate deficient in OmpK35/36 and PhoE. MICs to ceftolozane/tazobactam, cefotaxime, ceftazidime, cefepime, and meropenem were determined by E-test. Kp 23 and KPM 20 were characterized by Western blot and whole genome sequencing.

Results
Production of CMY-2 alone led to a resistant phenotype for ceftolozane/tazobactam, cefotaxime, and ceftazidime regardless of porin production (Figure 1). CMY-2 production in KPM 20 resulted in non-susceptibility to meropenem. Both clones were susceptible to cefepime. Production of CTX-M-14 and CTX-M-15 in Kp 23 resulted in only cefotaxime resistance. Production of CTX-M-14 and CTX-M-15 in KPM 20 resulted in isolates non-susceptible to all antibiotics tested.

Figure 1. MICs of K. pneumoniae clones against panel of β-lactam antibiotics.

Conclusion
When evaluating clinical isolates, it is impossible to determine the contribution of individual resistance mechanisms in the susceptibility pattern. This study demonstrated that resistance is not solely dependent on the β-lactamase produced and that the impact of porin deficiency varies with the antibiotic being evaluated. These data suggest that antibiotic selection may be more nuanced and that a broader range of therapeutics may be available given the appropriate diagnostic tools. Understanding the contributions of all resistance mechanisms is necessary to inform selection of the most appropriate antibiotic therapy.

Disclosures
Nancy D. Hanson, PhD, Merck (Grant/Research Support)
1231. In Vitro Activity of Aztreonam-Avibactam and Comparator Agents Against Enterobacterales from Patients with Lower Respiratory Tract Infections Collected During the ATLAS Global Surveillance Program, 2017-2019
Authors: Lob Sibylle , Kazmierczak Krystyna , Arhin Francis , Sahm Daniel F 
Published: December 2021

Abstract

Background
β-lactamase-producing Enterobacterales (Ebact) frequently co-carry resistance to antimicrobials from other classes, limiting treatment options. Avibactam (AVI) inhibits class A, class C, and some class D serine β-lactamases, while aztreonam (ATM) is refractory to hydrolysis by class B metallo-β-lactamases (MBLs). ATM-AVI is being developed for use against drug-resistant isolates of Ebact, especially those co-producing MBLs and serine β-lactamases. This study evaluated the in vitro activity of ATM-AVI and comparators against Ebact collected in 2017-2019 from patients with lower respiratory tract infections (LRTI) as part of the Antimicrobial Testing Leadership and Surveillance (ATLAS) program.

Methods
Non-duplicate clinical isolates were collected in 52 countries in Europe, Latin America, Asia/Pacific (excluding mainland China and India), and Middle East/Africa. Susceptibility testing was performed by CLSI broth microdilution and interpreted using CLSI 2021 and FDA (tigecycline) breakpoints. ATM-AVI was tested at a fixed concentration of 4 µg/mL AVI. MDR was defined as resistant (R) to ≥3 of 7 sentinel drugs: amikacin, aztreonam, cefepime, colistin, levofloxacin, meropenem, and piperacillin-tazobactam. PCR and sequencing were used to determine the β-lactamase genes present in all isolates with meropenem MIC &gt;1 µg/mL, and Escherichia coli, Klebsiella spp. and Proteus mirabilis with ATM or ceftazidime MIC &gt;1 µg/mL.

Results
ATM-AVI was active in vitro against Ebact isolates from LRTI (MIC90, 0.25 µg/mL), with 99.97% of isolates inhibited by ≤8 µg/mL of ATM-AVI, including 100% of isolates that produced MBLs. ATM-AVI tested with MIC90 values of 0.5 µg/mL against subsets of cefepime-nonsusceptible (NS), meropenem-NS, amikacin-NS, colistin-resistant, and MBL-positive Ebact (Table). The tested β-lactam comparators showed susceptibility of &lt; 78% against these subsets of resistant isolates.
Results Table

Conclusion
Based on MIC90 values, ATM-AVI was the most potent agent tested against drug-resistant and MBL-positive subsets of Ebact collected from LRTI. The promising in vitro activity of ATM-AVI warrants further development of this combination for treatment of LRTI caused by drug-resistant Ebact.

Disclosures
Sibylle Lob, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Krystyna Kazmierczak, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Francis Arhin, PhD, Pfizer, Inc. (Employee) Daniel F. Sahm, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor)
1233. Serious Toxicities During Antimicrobial Therapy for Disseminated Nocardia Infection in Solid Organ Transplant Recipients
Authors: Saling Christopher , Kasule Sabirah N , Vikram Holenarasipur R 
Published: December 2021

Abstract

Background
Management of disseminated Nocardia (NC) infection in transplant recipients requires prolonged antimicrobial therapy. Treatment can be particularly challenging if NC is resistant to standard agents. Drug toxicities can further limit options. We present a series of transplant patients with multi-drug resistant, disseminated NC infection complicated by serious adverse reactions to sequential antimicrobials.

Methods
This is a prospective review monitoring response to treatment of disseminated NC as well as adverse events to therapies.

Results
The first case is a 66-year old heart transplant patient who presented with fever and cough. Investigations revealed N. otitidiscaviarum lung lesion and multiple brain abscesses. Trimethoprim-sulfamethoxazole (TMP-SMX) and linezolid were started empirically. NC was fully susceptible to linezolid only, and intermediate to quinolones and tobramycin. Linezolid was switched to ciprofloxacin due to ongoing cytopenia, and dose of TMP-SMX was reduced due to renal insufficiency. Repeat brain MRI showed enlarging abscesses; regimen was changed to linezolid and moxifloxacin. Severe peripheral neuropathy led to linezolid discontinuation and initiation of high-dose doxycycline plus moxifloxacin. One year into therapy, he presented with a large aortic dissection. His long-term quinolone therapy was felt to be contributory. He underwent aortic stent placement and remains on doxycycline monotherapy. The second case is a 74-year old female renal transplant patient who presented with fevers. A perinephric abscess was found which grew N. farcinica resistant to floroquinolones and clarithromycin, and intermediate to doxycycline. Further imaging also revealed pulmonary and brain involvement. TMP-SMX was started but soon switched to linezolid due to acute kidney injury. One month later she presented with severe thrombocytopenia and subdural hematoma thought to be secondary to linezolid. She died despite surgery.

Conclusion
This series illustrates challenges encountered in the treatment of disseminated NC infection in transplant recipients. Multidrug resistant NC coupled with serious toxicities of therapies often severely limits treatment options. Counseling patients and closely monitoring for adverse events is essential.

Disclosures
All Authors: No reported disclosures
1234. Can Susceptibility to One Carbapenem be Conferred to Another? Frequency of Discordance in Gram-negative Clinical Isolates
Authors: Ku Pam M , Hobbs Diana A , Gilmore Melissa , Hobbs Athena L 
Published: December 2021

Abstract

Background
Carbapenem-Resistant Enterobacterales (CRE) and Carbapenem-Resistant Pseudomonas aeruginosa (CRPA) can exhibit resistance to one carbapenem while remaining susceptible to another. While case reports describing discrepant carbapenem susceptibilities are available, the authors are unaware of any literature reporting aggregate carbapenem susceptibility discrepancies at a hospital level.

Methods
Susceptibility data from April 1, 2017 - December 31, 2017 was extracted through an antibiogram report for a 706-bed hospital. Ertapenem, imipenem-cilastatin, and meropenem susceptibilities were captured and compared for common Enterobacterales and Pseudomonas aeruginosa. Organism identification was performed using Matrix Assisted Laser Desorption Ionization-Time of Flight (MALDI-TOF) mass spectrometry. Antibiotic susceptibility testing was performed using BD PhoenixTM. Carbapenem susceptibilities were interpreted using the most updated Clinical and Laboratory Standards Institute (CLSI) breakpoints at the time of assessment (2021). Carbapenem discordance was defined as an organism being susceptible to one carbapenem and non- susceptible (intermediate or resistant) to another. Approval was obtained from the institution’s Institutional Review Board.

Results
Meropenem proved to be the most active antimicrobial for all organisms (Figure 1). Carbapenem susceptibility discordance ranged from 0%-23.8% (Table 1). There was a significant difference in the incidence of discordance between Enterobacterales and Pseudomonas aeruginosa isolates (2.6% vs. 6.1%, p &lt; 0.001). Of the 20 Pseudomonas aeruginosa isolates with discordant carbapenem susceptibilities, 70% were meropenem susceptible/imipenem non-susceptible and 30% were imipenem susceptible/meropenem non-susceptible. The most common site for discordance was urine for both Enterobacterales and Pseudomonas aeruginosa. However, while there was a significant rate of discordance between sites for Pseudomonas isolates, this was not the case for Enterobacterales (Table 2).
Figure 1: Carbapenem Susceptibility by Isolate

Table 1: Frequency of Carbapenem Discordance

Table 2: Frequency of Carbapenem Discordance by Site

Conclusion
Due to the wide range of susceptibility discordance, clinical implications can be drastic if an institution is relying on susceptibility of one carbapenem to confer susceptibility to another carbapenem.

Disclosures
All Authors: No reported disclosures
1237. Characterization and crystallization of OXA-935, a novel class D OXA-10-like beta-lactamase, found in Pseudomonas aeruginosa
Authors: Pincus Nathan B , Rosas-Lemus Monica , Gatesy Samuel W , Shuvalova Ludmilla , Minasov George , Satchell Karla , Brunzelle Joseph S , Lebrun-Corbin Marine , Ozer Egon A , Hauser Alan R , R Bachta Kelly E 
Published: December 2021

Abstract

Background
Recently, we described a collection of ST298 Pseudomonas aeruginosa (PA) isolates that caused a prolonged epidemic of XDR infections. Many of these contain derivatives of a new plasmid, pPABL048, that harbors an MDR integron, in1697. In1697 contains a series of antimicrobial resistance (AMR) genes, one of which is the class D β-lactamase blaOXA-10. Variants of blaOXA-10 have been described that confer both extended-spectrum β-lactamase (ESBL) and carbapenemase activity.

Methods
Of all ST298 isolates, three were resistant to ceftazidime (CTZ). Genomic comparison of in1697 in CTZ-resistant and CTZ-sensitive strains revealed that all three strains harbored a blaOXA-10 allele with two single nucleotide variations resulting in amino acid changes at positions 153 (F153S) and 157 (G157D). Using the NCBI database, we identified this allele as unique and defined this β-lactamase as OXA-935. OXA-935 shares the G157D variation with OXA-14 which is known to confer resistance to ceftazidime. We sought to characterize the function of OXA-935 and to determine the crystal structures of OXA-14 and OXA-935.

Results
Deletion of blaOXA-935 phenotypically converted all three strains to CTZ-susceptible. Expression of blaOXA-14 and blaOXA-935 conferred CTZ-resistance to laboratory PA strains PA01 and PA14. Determination of the crystal structures of OXA-14 (PDB code 7L5R) and OXA-935 (PDB code 7L5V) revealed that the F153S variant resulted in increased flexibility in the enzyme’s Ω loop. Conformational changes in the Ω loop likely contributed to the lack of carbamylation at lysine-70 (K70) observed in OXA-935. Carbamylation of K70 is known to be critical for enzymatic activity of class D β-lactamases.

Conclusion
OXA-935 is very similar to OXA-14; however, comparison revealed that the F153S variant has unique structural features and is functionally distinct. Despite these differences, both enzymes confer high-level CTZ resistance. As we increasingly rely on β-lactam antimicrobial therapy (e.g. ceftazidime, cefepime) and combination (e.g. ceftazidime-avibactam) therapy to treat MDR PA infections, it is critical that we continue to explore the mechanistic basis of β-lactam AMR in an effort to preserve existing treatments and design novel ones.

Disclosures
All Authors: No reported disclosures
1239. Ceftaroline versus Vancomycin as First-Line Therapy for MRSA Bacteremia
Authors: Kamath Meghan , Ma Ariel , Johns Scott T 
Published: December 2021

Abstract

Background
Beta-lactams have demonstrated superior outcomes over vancomycin in MSSA bacteremia. Despite this, studies of the anti-MRSA beta-lactam ceftaroline in MRSA bacteremia (MRSAB) are largely limited in size or focus on combination or salvage regimens. This study sought to further examine ceftaroline as first-line therapy for MRSAB.

Methods
This was a retrospective matched cohort study at the San Diego VA Medical Center between November 2010 and June 2020. Patients had to have received at least 72 hours of ceftaroline or vancomycin for MRSAB and less than 72 hours of prior MRSA therapy. Adjunct MRSA therapy was allowed only if routinely indicated for the infection (e.g. rifampin for prosthesis). Patients in the vancomycin group were matched 1:1 to patients in the ceftaroline group by age (+/- 10 years) and Pitt bacteremia score (+/- 1 point). The primary outcome was duration of bacteremia after initiation of MRSA therapy, including time on prior MRSA therapy.

Results
Fifteen patients were included in each group, with a median age of 65 years and Pitt bacteremia score of 0. Patients in the ceftaroline group were more likely to have CKD; to have been on a different MRSA agent prior to initiation of the study drug, with a median of 1 day of prior treatment; and to have been on adjunctive rifampin or clindamycin. Though not significant, more patients in the ceftaroline group also had endovascular sources, uncontrolled sources, and longer durations of therapy. The median duration of bacteremia after initiation of MRSA therapy did not significantly differ between ceftaroline and vancomycin (4 vs. 3 days, p = 0.806). In addition, 30-day all-cause mortality, in-hospital mortality, 90-day readmission or treatment failure, inpatient length of stay, total duration of bacteremia, and rate of adverse events did not significantly differ between groups.

Conclusion
This study suggests ceftaroline may be an appropriate first-line agent for the treatment of MRSA bacteremia with similar outcomes between groups despite the ceftaroline group likely experiencing more difficult-to-treat infections. However, it was not powered to detect differences between groups, and its retrospective nature has the potential to introduce bias. Prospective comparative studies are needed to corroborate these findings.

Disclosures
All Authors: No reported disclosures
1241. In Vivo Efficacy of Meropenem Against Metallo-ß-Lactamase (MBL)-Harboring Pseudomonas aeruginosa and Correlation to In Vitro Susceptibility Upon Addition of EDTA
Authors: Kois Abigail K , Asempa Tomefa E , Nicolau David P 
Published: December 2021

Abstract

Background
Prior investigations evaluating the predictive value of zinc-depleted media for MBL-susceptibility testing have focused on Enterobacterales. Therein, bacterial killing observed with meropenem (MEM) in vivo was concordant with its pharmacodynamic profile using MIC values determined in zinc-depleted media compared with conventional cation-adjusted Mueller-Hinton broth (CAMHB). This study aims to evaluate the exposure-response relationship of MEM against VIM- and NDM-harboring P. aeruginosa (PSA) using the murine thigh infection model and zinc-depleted MICs.

Methods
MBL-harboring PSA isolates (VIM n=11; NDM n=10) were tested both in vivo (neutropenic murine thigh infection model) and in vitro (broth microdilution). The 24h murine thigh study was conducted with treatment groups receiving a humanized MEM 2g q8h (3h infusion) dose. Six different zinc-limited media were prepared by the addition of EDTA at concentrations ranging from 3 to 300 mg/L to CAMHB. MEM MICs were determined in triplicate in conventional CAMHB and zinc-limited media. Time &gt; MIC values (generated in each zinc-depleted media) were then plotted against the change in 24h bacterial density count in an Emax model.

Results
Average 0 h bacterial densities were 5.21 ± 0.40 and 5.13 ± 0.81 log10 CFU/thigh for NDM and VIM isolates, respectively. MEM resulted in -0.09 CFU reduction to +3.69 CFU growth against NDM isolates. MEM resulted in -2.59 CFU reduction to +4.81 CFU growth against VIM isolates. All MEM MICs in conventional CAMHB were &gt;64 µg/mL for NDM and ranged from 8 to &gt;64 µg/mL for VIM isolates. Increasing EDTA concentrations resulted in several-fold MIC reductions and on average, a larger magnitude of reduction was observed among VIM- (6-fold) compared with NDM-harboring PSA (4-fold) in CAMHB-EDTA 300 mg/L relative to CAMHB. For both NDM- and VIM-harboring PSA, an Emax model with MICs generated in CAMHB+EDTA 30 mg/L (r2 = 0.88) provided the highest correlation with MEM in vivo activity compared with CAMHB (r2 = 0.55).

Conclusion
Results indicate that MIC values generated in conventional CAMHB do not appropriately characterize the in vivo efficacy of meropenem against MBL-harboring PSA, and addition of EDTA (30 mg/L) to CAMHB appears to be a viable option for in vitro testing of these organisms.

Disclosures
David P. Nicolau, PharmD, Abbvie, Cepheid, Merck, Paratek, Pfizer, Wockhardt, Shionogi, Tetraphase (Other Financial or Material Support, I have been a consultant, speakers bureau member, or have received research funding from the above listed companies.)
1242. Efficacy and Safety of Intravenous Fosfomycin for the Treatment of Multi-resistant Gram Negative Infections
Authors: Abdallah Tasneem , Elajez Reem , Ibrahim Tawheeda , Alimam Abeir , Omrani Ali S 
Published: December 2021

Abstract

Background
To describe the clinical use, efficacy and safety of intravenous (IV) fosfomycin in the treatment of infections caused by Gram-negative bacteria (GNB).

Methods
Hospitalized patients who received ≥48 hours of IV fosfomycin therapy during September 27, 2017 thru January 31, 2020 were included. The primary outcome was the proportion of subjects with clinical improvement at the end of IV fosfomycin therapy; defined as resolution of baseline signs and symptoms of infection.

Results
Thirty patients were included, of which 19 (63.3%) were males, and the median age was 63.5 years (interquartile range 46─73). Frequent risk factors for GNB infection included hospitalization (23, 76%), receipt of broad-spectrum antibiotics (15, 50%), and surgery (10, 33.3%), all within the preceding 90 days. Urinary tract infection (17, 56.7%) was the most common indication for use of IV fosfomycin, followed by bacteremia (4, 13.3), and skin and soft tissue infections (4, 13.3%). Kelbsiella pneumoniae (17, 56.7%), Escherichia coli (7, 23.3%) and Pseudomonas species (4, 13.3%) were the most common target pathogens. Almost all target pathogens (29, 96.7%) were resistant in vitro to ≥1 agent from ≥3 different antimicrobial classes. The primary outcome was achieved in 22 (73.3%) patients. The most frequently observed adverse events were hypokalemia (13, 43.3%) and hypernatremia (7, 23.3%). However, the majority of adverse events were classified as Grade 1 or Grade 2 severity.
Microbiological characteristics

The table describes microbiological characteristics of the isolated organism species, resistance pattern, development of fosfomycin resistance
Management outcomes and safety profile

The table describes percentage of primary outcome (clinical success ) along with safety profile and mortality rate

Conclusion
IV fosfomycin is a potentially effective and safe option for the treatment of patient with GNB infections.

Disclosures
All Authors: No reported disclosures