bluuebunny/crossref_metadata_2025 huggingface dataset:
1567. In Vitro Activity of Aztreonam-Avibactam and Comparator Agents Against Multidrug-Resistant Enterobacterales Collected Globally as Part of the ATLAS Surveillance Program, 2016-2018
Authors: Kazmierczak Krystyna , Arhin Francis , Stone Greg , Sahm Daniel F
Published: January 2021

Background

Avibactam (AVI) is a serine-β-lactamase inhibitor in development with aztreonam (ATM) for treatment of infections caused by drug-resistant Enterobacterales (Ent), especially carbapenem-resistant isolates co-producing serine- and metallo-β-lactamases (MBL), which are often resistant to agents from multiple drug classes. This study evaluated the in vitro activity of ATM-AVI and comparators against Ent collected globally as part of the Antimicrobial Testing Leadership and Surveillance (ATLAS) program.

Methods

44,671 non-duplicate clinical isolates were collected in 2016-2018 in 52 countries in Europe, Asia/Pacific (excluding China and India), Middle East/Africa, and Latin America. Susceptibility testing was performed by CLSI broth microdilution and interpreted using CLSI 2020 and FDA (tigecycline) breakpoints. ATM-AVI was tested at a fixed concentration of 4 µg/mL AVI. Drug-resistant phenotypes were defined as: multidrug resistant (MDR), resistant (R) to ≥3 of 7 sentinel agents (amikacin [AMK], ATM, cefepime [FEP], colistin [CST], levofloxacin [LVX], meropenem [MEM], piperacillin-tazobactam [TZP]); extensively drug resistant (XDR), susceptible to ≤2 sentinel agents; and pandrug resistant (PDR), non-susceptible to all sentinel agents. Isolates with MEM MIC >1 µg/mL were screened for β-lactamase genes by PCR and sequencing.

Results

14.9%, 4.3%, 3.7%, 1.3%, and 0.3% of Ent collected globally were MDR, XDR, MEM-R, MBL-positive, and PDR, respectively. ATM-AVI tested with MIC90 values of 0.12 µg/mL against all Ent and 0.5 µg/mL against subsets of resistant isolates (Table). On the regional level, similar values were observed against all (MIC90, 0.12 µg/mL) and resistant isolates (MIC90, 0.25-1 µg/mL) (not shown). The tested comparators, excluding TGC, showed percentages of susceptibility < 90% against regional and global subsets of resistant isolates. 99.97% (44658 of 44671) Ent, including all MBL-positive and PDR isolates, were inhibited by ≤8 µg/mL of ATM-AVI.

Table

Conclusion

Based on MIC90 values, ATM-AVI demonstrated potent in vitro activity against resistant and MBL-positive subsets of Ent collected globally. ATM-AVI could be an effective therapy for difficult-to-treat infections caused by drug-resistant Ent.

Disclosures

Krystyna Kazmierczak, PhD, IHMA (Employee)Pfizer, Inc. (Consultant) Francis Arhin, PhD, Pfizer, Inc. (Employee) Greg Stone, PhD, AztraZeneca (Shareholder, Former Employee)Pfizer, Inc. (Employee) Daniel F. Sahm, PhD, IHMA (Employee)Pfizer, Inc. (Consultant)Shionogi & Co., Ltd. (Independent Contractor)
1568. In Vitro Activity of Ceftazidime-Avibactam and Comparator Agents Against Enterobacterales and Pseudomonas aeruginosa Collected < 48 Hours and ≥48 Hours Post-Admission from Pediatric Patients, ATLAS Surveillance Program 2015-2018
Authors: Kazmierczak Krystyna , Stone Greg , Sahm Daniel F
Published: January 2021

Background

Ceftazidime-avibactam (CAZ-AVI) is a β-lactam/non-β-lactam β-lactamase inhibitor combination with in vitro activity against Enterobacterales (Ent) and Pseudomonas aeruginosa (Psa) carrying Class A, C and some Class D β-lactamases. We examined the in vitro activity of CAZ-AVI and comparators against presumed community-acquired (CA; cultured < 48 h after hospital admission) and hospital-acquired (HA; cultured ≥48 h post-admission) isolates collected from pediatric patients as part of the ATLAS surveillance program.

Methods

6023 non-duplicate isolates were collected in 50 countries in Europe (n=3122), Latin America (n=1220), Middle East/Africa (n=1007), and Asia/Pacific (excluding China; n=674) from patients (newborn to 17 y) with lower respiratory tract (LRTI; n=1641), urinary tract (UTI; n=1595), skin and soft tissue (SSTI; n=1027), intra-abdominal (IAI; n=949), and bloodstream (BSI; n=811) infections. Susceptibility testing was performed by CLSI broth microdilution and values were interpreted using CLSI 2020 breakpoints. CAZ-AVI was tested at a fixed concentration of 4 µg/mL AVI. Isolates with CAZ or aztreonam MICs ≥2 µg/mL (Escherichia coli, Klebsiella spp., Proteus mirabilis) or meropenem MICs ≥2 µg/mL (all Ent species) or ≥4 µg/mL (Psa) were screened for β-lactamase genes.

Results

The in vitro activity of CAZ-AVI exceeded that of meropenem and other tested β-lactams against Ent (98.5% susceptible (S)) and Psa (93.1% S) collected globally from pediatric patients (Table). Percentages of susceptibility to CAZ-AVI ranged from 96.8-99.3% among CA Ent from different infection types and were reduced 0.4-1.0% among HA isolates from SSTI, IAI and BSI. Susceptibility to CAZ-AVI was also similar (92.7-95.4% S) among CA Psa from different infection types and was reduced 0.1-4.4% among HA isolates. For both Ent and Psa, the lowest percentages of susceptibility to the tested β-lactams were observed among isolates from BSI, which included a higher proportion of isolates carrying extended-spectrum β-lactamases and/or carbapenemases than isolates from other infection types.

Table

Conclusion

CAZ-AVI could provide a valuable therapeutic option for treatment of CA and HA infections caused by Ent and Psa in pediatric patients.

Disclosures

Krystyna Kazmierczak, PhD, IHMA (Employee)Pfizer, Inc. (Consultant) Greg Stone, PhD, AztraZeneca (Shareholder, Former Employee)Pfizer, Inc. (Employee) Daniel F. Sahm, PhD, IHMA (Employee)Pfizer, Inc. (Consultant)Shionogi & Co., Ltd. (Independent Contractor)
130. Antimicrobial Stewardship Practices in Community Pharmacies Across the United States
Authors: Lee Yuman , Bradley Nicole , Trinh Saralinh
Published: January 2021

Background

Antimicrobial stewardship (AMS) in the community is essential as majority of antibiotic prescribing occurs in the community. Pharmacists are recognized by the Center for Disease Control and Prevention (CDC) as co-leaders for leading implementation efforts to improve antibiotic use. The purpose of this study is to evaluate current AMS practices in community pharmacies across the United States (US) and identify challenges.

Methods

A 15-item survey was created based on CDC’s Core Elements of Outpatient AMS to assess current policies and practices in place, as well as collect baseline demographics and pharmacists’ perceptions. A survey invite was posted on the Facebook group, Pharmacist Moms, in September 2019. Participation was voluntarily and anonymous.

Results

Participants included 61 community pharmacists from 25 states across the US. 88.5% work in a chain pharmacy with 54.1% in staff positions and 37.7% in management. 37.7% have been practicing for > 10 years, 36.1% for 6–10 years and 26.2% 5 or less years. Minimal responses met CDC’s Core Elements of AMS: commitment (27.9%), action (24.6%), tracking and reporting (14.8%), and education and expertise (23% for pharmacists, 9.8% for patients).

In regards to perception, 67.9% felt AMS is important in the community. 88.5% would participate in AMS if the opportunity were provided. 91.8% were unsure or had no plans to implement AMS within the next 2 years.

Common challenges include the lack of time/staff (83.6%), pushback from prescribers (68.9%), lack of leadership (57.4%), lack of financial incentives (52.5%), pushback from patients (52.5%), lack of pharmacist knowledge/training (39.3%), lack of funding/financial support (29.5%), lack of legal requirement (21.3%), lack of information technology support (19.7%), and lack of pharmacist interest (11.5%).

Current Trends of U.S. Community Pharmacies in Meeting CDC’s Core Elements of Outpatient Antimicrobial Stewardship

Challenges in Implementing Antimicrobial Stewardship in Community Pharamacies

Conclusion

Results from this study reveal the lack of AMS practices in community pharmacies. Pharmacists have a critical role in AMS, but many challenges exist in the community setting inhibiting the full potential of pharmacists in AMS efforts. This study highlights the importance and need for addressing these issues as regulations and strategies for AMS in community settings develop.

Disclosures

All Authors: No reported disclosures
1571. In Vitro Activity of Ceftazidime-Avibactam and Comparator Agents Against MDR Enterobacterales and Pseudomonas aeruginosa Collected in Latin America During the ATLAS Global Surveillance Program 2017-2018
Authors: Kazmierczak Krystyna , Lob Sibylle , Stone Greg , Sahm Daniel F
Published: January 2021

Background

Ceftazidime-avibactam (CAZ-AVI) is a β-lactam/non-β-lactam β-lactamase inhibitor combination that can inhibit class A, C and some class D β-lactamases. Resistance caused by these β-lactamases often results in multidrug-resistance (MDR). This study evaluated the in vitro activity of CAZ-AVI and comparators against MDR Enterobacterales and Pseudomonas aeruginosa isolates collected from patients in Latin America.

Methods

Non-duplicate clinical isolates were collected in 2017-2018 in 10 countries in Latin America. Susceptibility testing was performed using CLSI broth microdilution and interpreted using CLSI 2020 and FDA (tigecycline) breakpoints. MDR was defined as resistant (R) to ≥3 of 7 sentinel drugs: amikacin (AMK), aztreonam (ATM), cefepime (FEP), colistin (CST), levofloxacin (LVX), meropenem (MEM), and piperacillin-tazobactam (TZP).

Results

The activity of CAZ-AVI and comparators against all isolates and MDR subsets is shown in the table. MDR rates for the studied species ranged from 17.6% among E. cloacae to 31.0% among K. pneumoniae. CAZ-AVI was active against 99% of Enterobacterales isolates and maintained activity against 85-99% of MDR isolates of the examined species. Only tigecycline showed comparable or higher activity. Among P. aeruginosa, CAZ-AVI was active against 86% of all isolates and 45% of MDR isolates; no other studied drug was more active. The three most common MDR phenotypes among Enterobacterales were 1) R to ATM, FEP, and LVX (n=538, 50% of all MDR Enterobacterales; 100% susceptible (S) to CAZ-AVI), 2) R to all sentinel drugs except AMK and CST (n=112, 10% of all MDR isolates; 88% S to CAZ-AVI), and 3) R to ATM, FEP, LVX, and TZP (n=111, 10% of all MDR Enterobacterales; 100% S to CAZ-AVI). The three most common MDR phenotypes among P. aeruginosa were 1) R to all sentinel drugs except CST (n=70, 22% of all MDR isolates; 20% S to CAZ-AVI), 2) R to AMK, LVX, and MEM (n=33, 10% of all MDR isolates; 33% S to CAZ-AVI), and 3) R to all sentinel drugs except AMK and CST (n=30, 9% of all MDR isolates; 70% S to CAZ-AVI).

Table

Conclusion

These in vitro data suggest that CAZ-AVI can be an effective treatment option for infections caused by MDR Enterobacterales and P. aeruginosa collected in Latin America.

Disclosures

Krystyna Kazmierczak, PhD, IHMA (Employee)Pfizer, Inc. (Consultant) Sibylle Lob, PhD, IHMA (Employee)Pfizer, Inc. (Consultant) Greg Stone, PhD, AztraZeneca (Shareholder, Former Employee)Pfizer, Inc. (Employee) Daniel F. Sahm, PhD, IHMA (Employee)Pfizer, Inc. (Consultant)Shionogi & Co., Ltd. (Independent Contractor)
1572. Combination Cefuroxime and Sulopenem is active in vitro against Mycobacterium abscessus
Authors: Dousa Khalid M , Nguyen David C , Kurz Sebastian G , Taracila Magdalena A , Bethel Christopher , Bonomo Robert A
Published: January 2021

Background

Mycobacterium abscessus (Mab) is a highly drug-resistant nontuberculous mycobacteria (NTM). Efforts to discover new treatments for Mab infections are accelerating with a focus on cell wall synthesis proteins (L, D-transpeptidases, LdtMab1-5, and D, D-carboxypeptidase) that are targeted by combination β-lactam antibiotics. The US Food and Drug Administration (FDA) has granted Qualified Infectious Disease Product (QIDP) to the oral and intravenous (IV) formulations of Sulopenem (SUL). Data on SUL in vitro activity against Mab is currently unavailable. Here, we evaluated activity of SUL alone and in combination with Cefuroxime salt (CEF) against representative clinical isolates belonging to the Mab complex. Both CEF and SUL are available in oral formulation and can be considered as oral step-down therapy.

Methods

Minimum inhibitory concentrations (MICs) of SUL and CEF alone and in combination were determined using microdilution. Approximately 5 x 105 colony-forming units (CFU) per milliliter were inoculated into Middlebrook 7H9 Broth supplemented with 10% (vol/vol) oleic albumin dextrose catalase and 0.05% (vol/vol) Tween 80. CEF was added at fixed concentration of 4 µg/ml to serial dilutions of SUL. Mab isolates were incubated with test agents at 30 °C for 48 h, and MIC was defined as lowest antibiotic concentration that prevented visible bacterial growth.

Results

Fifty-five clinically derived and previously characterized isolates were tested in these assays. MIC50 and MIC90 of CEF is 16 and 32 ug/ml; MIC50 and MIC90 of SUL is 2 and 4 ug/ml, the range of MICs are as follows: CEF (8 → 64 ug/ml); SUL (1→8 ug/ml); and SUL and CEF at fixed 4 ug/ml (< 0.25 → 4 ug/ml). Combination SUL and CEF lowered MIC to < 0.25 ug/ml in 52 clinical isolate (Figure).

Fig. MIC distributions of cefuroxime salt, sulopenem, sulopenem with 4 μg/ml cefuroxime monohydrate against 55 Mab clinical strains

Conclusion

Our results support the emerging hypothesis that dual β-lactam therapy is a promising strategy in the treatment of serious Mab infections. Investigating the biochemical rationale for this combination will support the application to clinical trials.

Disclosures

Robert A. Bonomo, MD, Entasis, Merck, Venatorx (Research Grant or Support)
1576. Re-Evaluation of cefepime or piperacillin-tazobactam to Decrease Use of Carbapenems in ESBL-Producing Enterobacterales BloodStream Infections (REDUCE-BSI)
Authors: Vu Catherine H , Venugopalan Veena , Santevecchi Barbara A , Voils Stacy A , Cherabuddi Kartikeya , DeSear Kathryn
Published: January 2021

Background

The ideal therapy for treatment of bloodstream infections (BSI) due to ESBL-producing organisms is widely debated. Although prior studies have demonstrated efficacy of non-carbapenems (CBPNs) for ESBL infections, results from the MERINO study group found increased mortality associated with piperacillin/tazobactam (PT) when compared with meropenem for treatment of ESBL BSI. The goal of this study was to investigate patient outcomes associated with the use of CBPN-sparing therapies (PT and cefepime (CEF)) for ESBL BSI. The primary outcome was in-hospital mortality between non-CBPN (PT and CEF) and CBPN groups. Secondary outcomes included clinical cure, microbiologic cure, infection recurrence, and development of resistance.

Methods

This was a retrospective observational study of patients admitted to the hospital from May 2016 - May 2019 with a positive blood culture for an ESBL-producing organism. Patients receiving meropenem, ertapenem, PT, or CEF were included. Patients were excluded if < 18 years old, receiving antibiotics for < 24 hours, treated for a polymicrobial BSI, or receiving concomitant antibiotic therapy for another gram-negative (non-ESBL) infection.

Results

One hundred and fourteen patients were analyzed; 74 (65%) patients received CBPN therapy compared with 40 (35%) patients that received a non-CBPN (CEF N=30, PT N=10). There were no statistically significant differences in baseline characteristics between groups. The overall in-hospital mortality rate was 6% (N=7). Eight percent of patients (N=6) in the CBPN arm died compared to 3% (N=1) of patients in the non-CBPN arm, P = 0.42. No difference in mortality was detected between groups when evaluating subgroups with Pitt bacteremia score ≥4 (N=25), requiring ICU admission (N=50), non-genitourinary source (N=50), or by causative organism (N=76 E. coli; N=38 Klebsiella spp.). There was no difference between groups for secondary outcomes.

Conclusion

CEF and PT are reasonable options for the treatment of ESBL BSI and did not result in increased mortality or decreased clinical efficacy when compared to CBPNs in this cohort.

Disclosures

All Authors: No reported disclosures
1578. Treatments for complicated urinary tract infections (cUTI) caused by multidrug resistant (MDR) Gram-negative (GN) pathogens- a systematic review and network meta-analysis (NMA)
Authors: Reason Tim , Gill Karan , Longshaw Christopher , McCool Rachael , Wilson Katy , Lopes Sara
Published: January 2021

Background

Antimicrobial resistance is a major and growing threat to global public health. Cefiderocol (CFDC) is a new siderophore-cephalosporin with a wide activity spectrum covering all aerobic GN pathogens including all WHO critical priority pathogens, that was recently approved by FDA for the treatment of GN cUTI in susceptible organisms. We aim to understand the relative efficacy and safety of current treatment options for cUTI caused by MDR GN pathogens.

Methods

We conducted a systematic review to identify all relevant trials that investigated the efficacy and safety of antimicrobial regimens, for the treatment of GN pathogens in cUTI. Outcomes of interest included clinical cure and microbiological eradication (ME) at time of cure (TOC) and sustained follow up (SFU), and safety. Evidence networks were constructed using data for outcomes of interest and analyses were conducted in a frequentist framework using NMA methods outlined by the NICE decision support unit using the netmeta package in R.

Results

A total of 5 studies, 6 interventions and 2,349 randomised patients were included in the final analysis. Interventions included CFDC, imipenem-cilastatin (IPM-CIL), ceftazidime-avibactam (CAZ/AVI), doripenem (DOR), levofloxacin and ceftolozane-tazobactam (CEF/TAZ). Trials included predominantly Enterobacterales, and Pseudomonas aeruginosa and very few Acinetobacter baumannii. The patient population presented some clinical differences across trials, which were not adjusted for the NMA. Overall, there were numerical differences (especially in endpoints at SFU favouring CFDC), but all treatments showed similar efficacy and safety, with exception of higher ME rate at TOC for CFDC vs IPM, Table 1, also observed at SFU, consistent with the data from the individual clinical trial.

Table 1- Results for microbiological eradication

Table 1- Results for microbiological eradication

Conclusion

This NMA, showed superiority of CFDC vs IPM-CIL in ME at TOC and SFU and similar efficacy and safety vs all other comparators, with numeric differences favouring CFDC for outcomes at SFU. These traditional methodologies for NMA, are only valid within a similar pathogens pool and population across the trials, and may not reflect the full value of breadth of coverage that new therapeutic options bring for the treatment of MDR GN pathogens.

Disclosures

Tim Reason, PhD, Shionogi (Consultant) Karan Gill, MSc, Shionogi BV (Employee) Christopher Longshaw, PhD, Shionogi B.V. (Employee) Rachael McCool, PhD, York Health Economics Consortium (Employee, YHEC was commissioned by Shionogi to conduct the systematic review) Katy Wilson, PhD, York Health Economics Consortium (Employee, Shionogi commissioned YHEC to conduct the systematic review) Sara Lopes, PharmD, Shionogi BV (Employee)
1579. Burkholderia Returns: Are Two Drugs Better or Back to Bactrim?
Authors: Hedvat Jason , Kubin Christine J , Mehta Monica
Published: January 2021

Background

Trimethoprim-sulfamethoxazole (T/S) and levofloxacin are considered first line agents for the treatment of Burkholderia cepacia complex (Bcc). Combination therapy (CT) is frequently utilized despite limited clinical evidence supporting this. The objective of this study is to compare outcomes associated with different regimens for the treatment of Bcc infections.

Methods

This is a retrospective cohort study in non-cystic fibrosis adult patients with infection caused by Bcc from 2015 to 2019. The primary outcome is the composite of overall treatment failure defined as clinical failure, microbiologic failure, or mortality at 30 days. Secondary outcomes include mortality, clinical failure, microbiological failure, development of resistance, recurrence, and safety. Comparisons were performed using Chi-squared or Fischer’s exact test for categorical variables and Student’s t test or the Mann-Whitney U test for continuous variables, as appropriate. Multivariable logistic regression analysis was used to identify independent risk factors for overall treatment failure.

Results

Sixty-eight patients were included, 50 (74%) received monotherapy (MT) and 18 (26%) received CT. MT regimens included meropenem (n=19), ceftazidime (n=15), T/S (n=10), and other (n=6). Various combination regimens were utilized. MT recipients were significantly older, more likely to have renal disease, less likely to have an immunosuppression, and had a higher severity of illness. The most common site of infection was respiratory (78%). No difference was found for overall treatment failure between MT and CT (36.0% vs. 38.9%; p=0.947). No differences were found in the secondary outcomes (Table 1). Overall treatment failure did not differ by treatment regimens utilized. On multivariable analysis controlling for age, renal disease, CCI, immunosuppression, ICU admission, SOFA score, and receipt of MT, only SOFA score was associated with treatment failure [OR 1.43 (95% CI 1.15 to 1.77); p=0.001] and not MT [OR 1.22 (95% CI 0.25 to 5.97); p=0.808].

Table 1: Treatment Outcomes – MT versus CT

Conclusion

There were no differences in outcomes between MT and CT groups for the treatment of Bcc infection. Treatment outcomes appeared to be driven primarily by disease severity. Additional studies are needed to identify the optimal treatment regimens.

Disclosures

All Authors: No reported disclosures
1584. In Vitro Activity of Imipenem/Relebactam against Gram-Negative Pathogens from Patients with Bloodstream Infections in the United States and Canada – SMART 2018
Authors: Lob Sibylle , Hackel Meredith , Young Katherine , Motyl Mary , Sahm Daniel F
Published: January 2021

Background

Relebactam (REL) inhibits class A and C β-lactamases, including KPC, and was approved in the United States combined with imipenem (IMI) and cilastatin for complicated urinary tract and intraabdominal infections. We evaluated the activity of IMI/REL against non-Morganellaceae (NME) and P. aeruginosa collected as part of the global SMART surveillance program from patients with bloodstream infections (BSI) in the US and Canada.

Methods

In 2018, 24 US and 8 Canadian hospitals each collected up to 50 consecutive aerobic or facultative gram-negative pathogens from patients with BSI. MICs were determined using CLSI broth microdilution and interpreted with 2020 CLSI breakpoints. Multidrug-resistance (MDR) was defined as resistance to ≥3 of the following sentinel drugs: amikacin, aztreonam, cefepime, ceftazidime (NME only), ciprofloxacin, colistin, imipenem, and piperacillin/tazobactam.

Results

The 5 most common species among 1463 collected BSI isolates were E. coli (46.9%), K. pneumoniae (16.0%), P. aeruginosa (8.5%), P. mirabilis (4.8%), and E. cloacae (4.3%). Susceptibility to IMI/REL and comparators of selected species and subsets of resistant phenotypes is shown in the table.

IMI/REL was active against 99.8% of NME isolates; only meropenem, ceftazidime/avibactam, and amikacin showed comparable activity. Per 2020 CLSI guidelines, Enterobacterales and P. aeruginosa isolates are no longer considered susceptible to colistin. IMI/REL maintained activity against 89-100% of NME isolates that were nonsusceptible (NS) to β-lactams or MDR. Among P. aeruginosa, IMI/REL was active against 94.4% of isolates; a susceptibility rate only exceeded by amikacin. The addition of relebactam lowered the MIC90 for P. aeruginosa from 16 µg/mL to 1 µg/mL. IMI/REL maintained activity against 40-77% of P. aeruginosa isolates NS to β-lactams or MDR; susceptibility rates only exceeded by amikacin.

Susceptibility to IMI/REL was similar in the US (99.8% of NME [n=846]; 93.8% of P. aeruginosa [n=96]) and Canada (99.7% of NME [n=339]; 96.4% of P. aeruginosa [n=28]).

Table

Conclusion

In the US and Canada, IMI/REL could provide an important treatment option for patients with BSI caused by resistant gram-negative organisms.

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)
1585. Stenotrophomonas maltophilia Infections and Approaches to Treatment
Authors: Caffrey Aisling , Appaneal Haley J , Lopes Vrishali , LaPlante Kerry
Published: January 2021

Background

Current knowledge of the epidemiology of Stenotrophomonas maltophilia is limited to studies from several small international medical centers. Additionally, real-world approaches to treatment are not well described.

Methods

We included admissions to any Veterans Affairs (VA) medical center nationally, with positive S. maltophilia cultures collected from any culture site between January 2010 and April 2019. We reviewed epidemiologic factors of clinical characteristics and treatment. Treatment was assessed by mapping out all antibiotic exposures each day, and identifying differences (heterogeneity) in the antibiotics used and duration of their use.

Results

Over the study period, we identified 8,225 hospital admissions with positive S. maltophilia cultures. Patients were older (mean age 68.2 year) and male (97.6%), with 25.8% in the intensive care and 56.1% admitted from other healthcare settings. Respiratory cultures were most common (47.4%), followed by urine (21.4%), skin and soft tissue (17.4%), and blood (5.1%). Admissions were mostly 11 days long (median), with an inpatient mortality rate of 13.9%.

The median time to culture collection from admission was day 3 of the hospitalization, and the median time to culture completion was 4 days. Changes in therapy occurred before culture completion for 67.3% of admissions. Most admissions utilized different treatment approaches (antibiotic drug and duration treatment heterogeneity 89.7%), with a median of 4 changes in therapy. Fluroquinolones were utilized in 40.6% of admissions (initiated median 4 days from admission) and sulfamethoxazole/trimethoprim in 26.3% (initiated median 7 days from admission). Inpatient mortality was significantly higher among those with changes in therapy versus those without changes (15.0% vs 5.7%, p< 0.0001), and among those without changes, mortality was significantly higher with monotherapy versus combination therapy (16.2% vs 2.6%, p< 0.0001).

Conclusion

Among more than 8,000 admissions with positive S. maltophilia cultures in the VA nationally, identification of the organism and targeted therapy did not occur until 4-7 days from admission. Differences in clinical outcomes were observed among the different treatment approaches.

Disclosures

Aisling Caffrey, PhD, Merck (Research Grant or Support)Pfizer (Research Grant or Support)Shionogi (Research Grant or Support) Haley J. Appaneal, PharmD, Shionogi, Inc. (Research Grant or Support) Kerry LaPlante, PharmD, Merck (Advisor or Review Panel member, Research Grant or Support)Ocean Spray Cranberries, Inc. (Research Grant or Support)Pfizer Pharmaceuticals (Research Grant or Support)Shionogi, Inc. (Research Grant or Support)
1588. Activity of Imipenem/Relebactam Against Clinical Isolates of P. aeruginosa and K. pneumoniae Collected in Asia/Pacific Countries – SMART 2016-2018
Authors: Lob Sibylle , Kazmierczak Krystyna , Chen Wei-Ting , Khan Tsz Kin , Young Katherine , Motyl Mary , Sahm Daniel F
Published: January 2021

Background

Relebactam (REL) inhibits class A and C β-lactamases and was approved in the USA in combination with imipenem (IMI) and cilastatin for the treatment of complicated intraabdominal and urinary tract infections. We evaluated the activity of IMI/REL against clinical isolates collected in Asia/Pacific as part of the global SMART surveillance program.

Methods

In 2016-2018, 56 clinical laboratories each collected up to 250 consecutive, aerobic and facultative gram-negative pathogens from various infection sources per year. Susceptibility was determined using CLSI broth microdilution and CLSI breakpoints. IMI-nonsusceptible isolates (except from India) were screened for β-lactamase genes.

Results

Among 5501 K. pneumoniae and 4362 P. aeruginosa isolates, 46.6% and 65.3%, respectively, were collected from patients with lower respiratory tract infections, 25.6% and 17.1% from intraabdominal infections, 19.9% and 13.9% from urinary tract infections, and 7.2 and 2.9% from bloodstream infections. No infection source was specified for 0.7% of isolates from either species. 90.7% of collected K. pneumoniae isolates were IMI/REL-susceptible, ranging from 56.8% in India and ~80% in Thailand and Vietnam (~16% MBL-positive) to ≥97% in 7 countries (0-2% MBL-positive). 28.6% (202/707) of IMI-nonsusceptible K. pneumoniae were IMI/REL-susceptible. Of the 425 molecularly characterized IMI-nonsusceptible K. pneumoniae, 187 (44.0%) were MBL/OXA-48-like negative and 83.4% of these (156/187) were IMI/REL-susceptible; 82 isolates (19.3%) were KPC-positive and 91.5% of these (75/82) were IMI/REL-susceptible.

The table shows percent susceptible and percent MBL-positive among all collected P. aeruginosa isolates. 74.3% of IMI-nonsusceptible P. aeruginosa (n=1236) were IMI/REL-susceptible.

Table

Conclusion

IMI/REL was active against 91% of K. pneumoniae and 89% of P. aeruginosa isolates collected in Asia/Pacific overall, with higher activity in countries with lower MBL-positive rates. IMI/REL promises to be an important treatment option for IMI-nonsusceptible MBL-negative isolates, including KPC-producing K. pneumoniae.

Disclosures

Sibylle Lob, PhD, IHMA (Employee)Pfizer, Inc. (Consultant) Krystyna Kazmierczak, PhD, IHMA (Employee)Pfizer, Inc. (Consultant) Wei-Ting Chen, MD, Merck, Sharp & Dohme, Taiwan (Employee) Tsz Kin Khan, PhD, Merck, Sharp & Dohme, Hong Kong (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)
1591. Antibiotic Utilization Trends in Veterans Affairs (VA) Patients with Carbapenem Resistant Enterobacteriaceae (CRE) Infections
Authors: Traversa Alfredo , Poggensee Linda , Wilson Geneva M , Suda Katie J , Evans Charlesnika T , Patel Ursula , Fitzpatrick Margaret A
Published: January 2021

Background

Carbapenem-resistant Enterobacteriaceae (CRE) are classified as an “urgent threat” to public health. Historically, colistin and tigecycline had been considered the drugs of choice for CRE infections, while other agents such as aminoglycosides and carbapenems had been used as adjunctive therapy. However, the FDA approval of ceftazidime-avibactam in 2015, meropenem-vaborbactam in 2017, and plazomicin in 2018 has expanded treatment options. Our purpose was to assess trends in CRE treatment for “new” antibiotics (ceftazidime-avibactam, meropenem-vaborbactam, plazomicin) as compared with other antibiotics with CRE activity.

Methods

This was a retrospective cohort study describing treatment of CRE blood stream infections (BSI) across 134 VA facilities from 2012-2018. Patients were censored at their first positive blood culture with CRE. Categorical data was assessed with a Fisher’s exact test or chi-square test. Trends test and logistic regression were used to describe changes in CRE treatment over time.

Results

724 patients with positive blood cultures for CRE were identified during the study period. Most patients were male (94%), white (32%) or Hispanic (38%), and the mean age was 71.5+11.9. Of those patients that received antibiotics (N=697), 53.4% carbapenems, 40.3% received aminoglycosides, 39.3% received polymyxins, 32.9% penicillins, 32.6% extended spectrum cephalosporins, 26.1% fluoroquinolones, 11.6% ceftazidime/avibactam, and 0.4% ceftolazone/tazobactam. Over the study period, there was decreased utilization of aminoglycosides (P < 0.0026) and colistin (P< 0.002) and increases in extended spectrum cephalosporins (P < 0.001) and ceftazidime/avibactam (P < 0.001).

Conclusion

Utilization of “older” agents such as aminoglycosides and polymyxins for the treatment of CRE blood stream infections is decreasing in the VA. Treating CRE with ceftazidime/avibactam, a newly approved antibiotic, and extended spectrum cephalosporins are increasing.

Disclosures

All Authors: No reported disclosures
1593. Antimicrobial Activity of Ceftazidime-Avibactam and Comparator Agents Against OXA-48 β-lactamase–Producing Enterobacterales Collected in International Medical Centers, Including the United States, in 2017–2018
Authors: Lin Lynn-Yao , Debabov Dmitri , Chang William
Published: January 2021

Background

OXA-48 is a carbapenemase with low-level hydrolytic activity toward cephalosporins. This study evaluated in vitro activities of ceftazidime-avibactam (CAZ-AVI), meropenem (MEM), meropenem-vaborbactam (MVB), ceftolozane-tazobactam (C/T), and other antimicrobial agents against 113 OXA-48-producing Enterobacterales with multiple resistance mechanisms collected in a 2017–2018 global surveillance program.

Methods

Nonduplicate clinical isolates of 113 Enterobacterales were collected from medical centers in 25 countries in 2017–2018. In vitro susceptibility tests were performed by broth microdilution with a custom-made panel consisting of CAZ-AVI, ceftazidime (CAZ), MEM, MVB, C/T, colistin (COL), gentamicin (GEN), levofloxacin (LEV), and amikacin (AMK). Whole genome sequencing or quantitative PCR data were used to analyze resistance mechanisms, such as OXA-48, extended-spectrum β-lactamase (ESBL), original-spectrum β-lactamase (OSBL), and AmpC β-lactamase. Clinical and Laboratory Standards Institute breakpoints were applied for susceptibility interpretations.

Results

Of 113 OXA-48–producing clinical isolates, 20 carried OXA-48 alone. The remaining 93 isolates carried additional β-lactamases, including 63 with ESBL (CTX-M-15) + OSBL (SHV, TEM), 15 with AmpC (DHA, AAC, CMY) + ESBL (CTX-M-15), and 15 with OSBL (SHV, TEM). 99.1% (all but 1) of all isolates tested were susceptible to CAZ-AVI, whereas 71.7%, 17.7%, and 14.2% were susceptible to MVB, MEM, and C/T, respectively. Among isolates harboring multiple resistance mechanisms (OXA-48 + ESBL + OSBL; n=63), 98.4%, 69.8%, 11.1%, and 7.9% were susceptible to CAZ-AVI, MVB, MEM, and C/T, respectively. Among isolates carrying OXA-48 + AmpC + ESBL + OSBL (n=15), 100%, 66.7%, 13.3%, and 13.3% were susceptible to CAZ-AVI, MVB, MEM, and C/T, respectively (Table). Aminoglycosides (AMK and GEN) and other β-lactams (eg, CAZ) were 20%–90% active against these isolates. COL was the second most effective comparator, inhibiting 83.2% of these isolates.

Table

Conclusion

CAZ-AVI was the most effective agent in this study compared with other antibiotics, including β-lactams, β-lactam–β-lactamase inhibitor combinations, aminoglycosides, and COL, against OXA-48-producing Enterobacterales carrying multiple β-lactamases.

Disclosures

Lynn-Yao Lin, MS, AbbVie (Employee) Dmitri Debabov, PhD, AbbVie (Employee) William Chang, BS, AbbVie (Employee)
1594. Antimicrobial Resistance Monitoring through the ATLAS Global Surveillance Program 2012-2018
Authors: Hackel Meredith , Sahm Daniel F , Dowzicky Michael
Published: January 2021

Background

Antimicrobial resistance is an increasingly serious threat to global public health. The Antimicrobial Testing Leadership and Surveillance (ATLAS) program has provided reliable, global, regional and local in vitro susceptibility data, including mechanisms of resistance, since 2004. In this analysis, data from the ATLAS program are used to measure the in vitro activity of several key gram-negative/gram-positive agents against major global pathogens.

Methods

A total of 251,837 gram-negative and 132,363 gram-positive non-duplicate, clinical isolates were collected from multiple infection sources from 743 unique sites in 74 countries during 2012-2018 in the ATLAS program. Identification was confirmed to the species level using MALDI-TOF spectrometry. Only one clinically relevant causative isolate per patient was accepted into the study. MICs were determined by broth microdilution following CLSI guidelines and interpreted using 2020 CLSI breakpoints. Phenotypic ESBL screening and confirmatory testing were performed using the CLSI M100 method.

Results

The in vitro activities of selected antimicrobial agents are provided in the table below. Based on percent susceptibility, ceftazidime-avibactam, amikacin, tigecycline, meropenem, and ceftolozane-tazobactam were the most active agents against most gram-negative isolates. The CRE rate among Enterobacterales isolates was 3.2%, with tigecycline and ceftazidime-avibactam the most active among this resistant subgroup. Ceftazidime-avibactam, ceftolozane-tazobactam, and amikacin were the most active agents against Pseudomonas aeruginosa. Ceftaroline, linezolid, tigecycline and vancomycin all showed good activity against gram-positive isolates.

Table

Conclusion

Ceftazidime-avibactam, ceftolozane-tazobactam, tigecycline, meropenem, and amikacin all showed good activity against a global collection of Enterobacterales. Ceftaroline, tigecycline, linezolid and vancomycin all exhibited excellent activity against gram-positive isolates. Continued monitoring of susceptibility patterns among common pathogens will provide useful information for determining treatment strategies.

Disclosures

Daniel F. Sahm, PhD, IHMA (Employee)Pfizer, Inc. (Consultant)Shionogi & Co., Ltd. (Independent Contractor) Michael Dowzicky, MS, M.T. A.S.C.P., Pfizer, Inc. (Employee)
1596. Ceftolozane/tazobactam (Zerbaxa) for the Treatment of Pseudomonas aeruginosa (PSA) Bacteremia: A Systematic Literature Review (SLR)
Authors: Dillon Ryan J , Khankhel Zarmina S , De Anda Carisa , Bruno Christopher , Puzniak Laura A
Published: January 2021

Background

Bacteremia is a significant cause of morbidity and mortality. Several studies have shown this burden to increase among patients with multidrug resistant (MDR) PSA, and in those treated with inappropriate empiric therapy. Ceftolozane/tazobactam (C/T) is a combination of a novel antipseudomonal cephalosporin and an established β-lactamase inhibitor approved for the treatment of complicated urinary tract infection, complicated intra-abdominal infection and hospital-acquired and ventilator-associated bacterial pneumonia. In the absence of specific bacteremia clinical trial data; the aim of this study is to describe all published evidence relating to C/T for the treatment of Gram negative bacteremia.

Methods

This SLR includes all published evidence from December 2015 to March 2020 searched via the OVID platform: EMBASE, MEDLINE, and MEDLINE In-Process. In addition, data published (2018-2019) from the European Society of Clinical Microbiology and Infectious Diseases and Infectious Disease Week Congresses were included. Eligible publications were on adult patients treated with C/T reporting any clinical outcome where data were reported specifically for the bacteremia population.

Results

The SLR identified 1,455 citations, of which 24 publications representing 23 unique studies met eligibility criteria. This included primary and secondary bacteremia. Ten studies included patients with primary bacteremia, only 7 of which reported results specific to primary bacteremia patients. Despite heterogeneity in study design, patient and treatment characteristics, and a lack of detailed reporting; the majority of studies focused on MDR/ extensively drug resistant (XDR) infections (range: 68.3%-100%). Clinical success/ cure ranged from 33%-100%, with 6/7 studies at >85%; 30-day mortality from 0%-67%, with 3/7 studies at 0% (Table 1).

Table 1. Clinical Outcomes reported among Primary Bacteremia population(s)

Conclusion

Although the number of C/T treated patients was small, favorable clinical outcomes were observed, even among highly resistant PSA infections. Heterogeneity was ubiquitous, with diverse and complex patient profiles identified. Further studies where outcomes are stratified by bacteremia status and by timing of C/T treatment are needed.

Disclosures

Ryan J. Dillon, MSc, Merck & Co., Inc., (Employee) Carisa De Anda, PharMD, Merck & Co Inc, (Employee) Christopher Bruno, MD, Merck & Co., Inc. (Employee) Laura A. Puzniak, PhD, Merck (Employee)
1599. Clinical Outcomes for Patients Treated with Fluoroquinolones for Bacteremia Caused by Enterobacteriaceae Reclassified as Not Susceptible by Updated CLSI Breakpoints
Authors: Fleischner Zachary , Szymczak Wendy , Weston Gregory
Published: January 2021

Background

Antibiotic resistance remains a pressing public health challenge. Antibiotic susceptibility testing is crucial to identify resistance and predict which antibiotics are most likely to be effective. In vitro minimum inhibitory concentrations (MICs) are interpreted using MIC breakpoints set for the United States by The Clinical and Laboratory Standards Institute (CLSI). In 2019 CLSI updated fluroquinolone (FQ) breakpoints for Enterobacteriaceae. Previously any isolate with an MIC ≤ 1 µg/mL of ciprofloxacin would be considered susceptible but based largely on pharmacokinetic/pharmacodynamic simulations the susceptibility breakpoint was revised to ≤ 0.25 µg/mL. However, the clinical relevance of this decision remains unclear.

Methods

All cases of Enterobacteriaceae bacteremia with isolates previously considered susceptible but reclassified as resistant (MIC = 1 µg/mL) in adults treated with FQs between 08/01/2018 and 07/31/2019 were identified. Demographics, clinical characteristics and outcomes were compared with an equal number of randomly selected isolates with an automated MIC reported as ≤ 0.5 µg/mL. Available stored isolates with a reported MIC of ≤ 0.5 µg/mL had manual E-testing performed to identify a more precise MIC.

Results

29 cases with an MIC = 1 μg/mL were compared with 29 controls with a MIC of ≤ 0.5. Only 3 cases and 1 control received FQs as empiric therapy, the remaining patients in each group were transitioned to FQ after a median of 4 days of other antibiotics. No significant difference was found for predetermined outcomes including 30 day mortality, escalation after starting FQ, length of hospital stay, and readmission in 30 days (see Table). No primary outcome was thought to be related to antibiotic failure. E-testing found no isolates with an MIC = 0.5 μg/mL.

Table 1

Conclusion

Patients with Enterobacteriaceae bacteremia treated with FQs for isolates reclassified as resistant had similar outcomes to those with lower MICs. While FQs are generally not recommended as first line empiric antibiotics, FQs may still be safe to use as stepdown therapy for isolates with a ciprofloxacin MIC = 1 μg/mL, particularly if the only alternative may be IV antibiotics. A larger study is needed to confirm this.

Disclosures

Gregory Weston, MD MSCR, Allergan (Grant/Research Support)
133. Creation of an Emergency Department (ED)-Specific Urine Antibiogram and Evaluation of Urinary Tract Infection (UTI) Prescribing Practices at a Tertiary Academic Medical Center
Authors: Broadbent Eleanor K , Caitlin Schanz , Boeser Kimberly D , Mason Jocelyn , Norton Laura E , Hirsch Elizabeth B
Published: January 2021

Background

Inpatient settings have been the focus of most antimicrobial stewardship (AS) practices; however, the Joint Commission has now published requirements for accredited ambulatory healthcare organizations to implement AS. This analysis aimed to create a urine isolate antibiogram and to evaluate microbiological data and prescribing practices for UTI patients in the ED.

Methods

This retrospective cohort study included adults admitted to either of two EDs at University of Minnesota Medical Center and diagnosed with a UTI between 1/1/2018 and 12/31/2018. Patients were excluded if subsequently admitted to an inpatient unit or if they had a repeat culture growing the same organism as the index isolate. Diagnosis of cystitis versus pyelonephritis was based on ICD-10 coding. Data including urinalysis and culture results, susceptibilities, empiric antibiotic selection, and readmissions were collected.

Results

Data from 350 isolates were collected for inclusion in the antibiogram. Patient characteristics corresponding to this isolate collection included 78.9% female, median age of 41 years, and 64.6% diagnosed with pyelonephritis. Escherichia coli was the most common organism (70%), followed by Klebsiella pneumoniae (5.4%) and Proteus mirabilis (4%). Combined susceptibilities of E. coli isolates from both EDs were: 49.4% ampicillin, 55.7% ampicillin/sulbactam, 69.8% sulfamethoxazole/trimethoprim, 83.7% ciprofloxacin (CIP), 85.7% cefazolin, 93.9% ceftriaxone, and 94.3% nitrofurantoin (NIT). The most common discharge antibiotics prescribed for cystitis patients were NIT (29.8%) and cephalexin (25%). Pyelonephritis patients were most frequently prescribed CIP (32.3%) and cefdinir (14.2%). Drug-bug mismatches occurred in 19.1% of patients (10.5% cystitis vs. 23.9% pyelonephritis). The rates of ED readmission within 96-hours and inpatient admission within 30 days, for any reason, were 4.3% and 9.1% respectively.

Conclusion

Based on the ED-specific urine antibiogram generated, NIT (cystitis) and CIP (pyelonephritis) could be considered first-line agents for empiric treatment of UTI at our institution. Drug-bug mismatches were more common in pyelonephritis patients. These data will be used to develop a treatment algorithm aimed at improving treatment of UTI in the ED.

Disclosures

Elizabeth B. Hirsch, PharmD, Merck (Grant/Research Support)Nabriva Therapeutics (Advisor or Review Panel member)