bluuebunny/crossref_metadata_2025 huggingface dataset:
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

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

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 < 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

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

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

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 > 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 >64 µg/mL for NDM and ranged from 8 to >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

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
1243. Eravacycline in Bacteremia: A Case Series
Authors: Andrade Justin A , Kosalka Robert , Truong James , Rosenberg Joshua R
Published: December 2021

Background

Eravacycline (ERV) is FDA-approved for the treatment of complicated intra-abdominal infections, but there is limited experience for non-FDA approved indications.

Methods

We present five cases that utilized ERV for treatment of bacteremia.

Results

Patient 1 in septic shock (SS) started on vancomycin (VAN) and ceftazidime-avibactam (CZA). Blood culture (BC) finalized to E. coli and regimen narrowed to CZA. On day 9, gram-positive cocci in chains in BC grew and VAN was added. BC finalized to VRE faecium and regimen was modified to ERV on day 12. Repeat BC on day 15 finalized to no growth with no recurrence of bacteremia until discharged (day 78). Patient 2 treated for MSSA bacteremia with cefazolin and subsequent K. pneumoniae VAP treated with ceftriaxone (CRO) (day 18-26). On day 27, meropenem (MEM) was initiated for gram-negative bacteremia and started on IV trimethoprim/sulfamethoxazole (TMP/SMX) the following day for pneumonia caused by TMP/SMX-susceptible S. maltophila. BC finalized on day 29 to S. maltophila resistant to TMP/SMX, regimen modified to ERV. Repeat BC on day 30 finalized to no growth and ERV was continued until day 42 with no recurrence of bacteremia; however, patient died on day 45. Patient 3 with renal failure and on day 11, CRO started for SBP prophylaxis. On day 13, switched to daptomycin and cefepime (FEP) as patient was febrile and BC repeated. BC finalized to VRE faecium and was started on ERV on day 17 and completed a 7-day course with no recurrence of bacteremia; however, patient died on day 34. Patient 4 initially treated for bacterial superinfection with CRO and azithromycin, and subsequent worsening pneumonia treated with VAN and MEM (day 10-17). On day 19, patient was febrile and treated with VAN and FEP until day 27. Repeat BC on day 29 finalized to VRE species and modified to ERV on day 32. ERV continued for a 7-day course and was discharged with no repeat BC obtained to confirm clearance. Patient 5 in SS started on VAN and MEM. On day 3, BC on admission finalized to VRE faecium and therapy switched to ERV. Repeat BC taken on day 3 after ERV initiation were negative. Discharged to complete two-week course of ERV.

Conclusion

ERV may be an option for bacteremia as demonstrated by clearance in four of five cases. More studies must be conducted as these reports show variable clinical outcomes.

Disclosures

Joshua R. Rosenberg, MD, Allergan/Abbvie (Consultant)La Jolla/Tetraphase (Consultant)Melinta (Consultant)Merck (Consultant)Paratek (Consultant)Sanofi (Consultant)Shionogi (Consultant)
1244. 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 2018-2019
Authors: Lob Sibylle , Hackel Meredith , Stone Gregory , Sahm Daniel F
Published: December 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 2018-2019 in 10 countries in Latin America. Susceptibility testing was performed using CLSI broth microdilution and interpreted using CLSI 2021 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 16.3% among E. cloacae to 35.7% among K. pneumoniae. CAZ-AVI was active against 98% of Enterobacterales isolates and maintained activity against 74-98% of MDR isolates of the examined Enterobacterales species. Only tigecycline showed higher activity. Among P. aeruginosa, CAZ-AVI was active against 87% of all isolates and 47% 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=544, 44.8% of all MDR Enterobacterales; 100% susceptible (S) to CAZ-AVI), 2) R to ATM, FEP, LVX, and TZP (n=150, 12.4% of all MDR Enterobacterales; 99.3% S to CAZ-AVI), and 3) R to all sentinel drugs except AMK and CST (n=145, 11.9% of all MDR isolates; 78.6% S to CAZ-AVI). The three most common MDR phenotypes among P. aeruginosa were 1) R to all sentinel drugs except CST (n=85, 19.7% of all MDR isolates; 24.7% S to CAZ-AVI), 2) R to all sentinel drugs except AMK and CST (n=42, 9.7% of all MDR isolates; 66.7% S to CAZ-AVI), and 3) R to AMK, LVX, and MEM (n=37, 8.6% of all MDR isolates; 24.3% S to CAZ-AVI).

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

Sibylle Lob, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Meredith Hackel, PhD MPH, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Gregory Stone, PhD, AztraZeneca (Shareholder, Former Employee)Pfizer, Inc. (Employee) Daniel F. Sahm, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor)
1249. Metabolomic Profile of Heterogeneous Vancomycin-Intermediate Staphylococcus aureus (hVISA) in Latin-American MRSA Isolates
Authors: Castro-Cardozo Betsy E , Cala Monica , Espitia-Acero Catalina , Rios Rafael , Leon Lizeth , Arias Cesar A , Rincon Sandra , Reyes Jinnethe , Diaz Lorena , Diaz Lorena
Published: December 2021

Background

Vancomycin (VAN) is a first-line therapeutic option in severe infections caused by MRSA in Latin-America (LA). Development of reduced susceptibility to VAN has been associated with multiple changes in genes encoding pathways for cell wall metabolism and envelope stress responses. Nevertheless, a detailed and coherent mechanistic model to explain the phenotype remains elusive. To gain further insights into the hVISA phenotype, we sought to explore the metabolomic profile of hVISA isolates from LA.

Methods

The undirected profile of intracellular S. aureus metabolites was analysed in four clinical isolates (two hVISA and two VSSA [Vancomycin susceptible S. aureus]) belonging to the Chilean/Cordobes clone-ST5 (the predominant hVISA lineage in LA), and two reference strains Mu3 and N315. The metabolites were obtained in mid-exponential growth phase in trypticase soy broth in five independent replicates. The metabolites were determined by reverse phase liquid chromatography and hydrophilic interaction. The metabolic profile was determined by variable importance in the projection score (VIP > 1). The differences between hVISA and VSSA were maximized by orthogonal partial least squares discriminant analysis (OPLS-DA) and the affected metabolic pathways were identified with MetaboAnalyst.

Results

Among the differences identified in the metabolic profiles of hVISA respect to VSSA, 69 metabolites were relevant. Of these, 47 were fatty acids (including glycerol), 7 amino acids and 6 nucleosides (Table 1). These changes mainly impact the biosynthesis of amino acids derived from pyruvate since tyrosine, valine and leucine, had a reduction of 34%, 57% and 41% in hVISA compared to VSSA, respectively, which suggests alterations of the acid cycle tricarboxylic (TCA). Additionally, a reduction in purine and pyrimidine metabolism in hVISA was identified with reduction of nucleosides and dinucleotides derived from the pentose phosphate pathway.

Table 1. Metabolites with higher VIP scores in the comparison of the hVISA and VSSA profile

Conclusion

We were able to observe metabolic alterations in TCA, pentose phosphate pathway and purine intermediates in hVISA-ST5 isolates. Our results support that gluconeogenesis and biosynthesis of carbohydrates and nucleic acids are the main pathways involved in the reduced susceptibility to VAN as reported in VISA isolates.

Disclosures

Cesar A. Arias, M.D., MSc, Ph.D., FIDSA, Entasis Therapeutics (Grant/Research Support)MeMed Diagnostics (Grant/Research Support)Merk (Grant/Research Support) Lorena Diaz, PhD , Nothing to disclose
1250. Development of Linezolid and Daptomycin Resistance in Vancomycin Resistant Enterococcus faecium (VRE) during prolonged treatment for Intraabdominal Abscess
Authors: Al-Heeti Omar , Joshi Tejas , Moore William Justin , Gatesy Samuel W , Pincus Nathan B , R Bachta Kelly E
Published: December 2021

Background

Vancomycin-resistant enterococci (VRE) are nosocomial pathogens with extensive intrinsic and acquired antimicrobial resistance (AMR) mechanisms. We report a case in which intraabdominal (IA) and blood cultures grew linezolid and daptomycin resistant VRE (DLVRE).

Methods

We report a case of DLVRE bacteremia after prolonged treatment with linezolid and daptomycin.

Results

The patient was a 65-year-old female with a history of multiple abdominal surgeries who presented for elective incisional hernia repair. Her post-operative course was complicated by the development of loculated IA abscesses. A drain was placed into the largest abscess, and aspiration cultures were polymicrobial containing vancomycin-resistant E. faecium (Isolate 1). The patient was treated meropenem, fluconazole and linezolid for 6 weeks. Clinical and radiographic improvement was achieved. However, 4 days after competing antibiotics she developed recurrent abdominal pain and a leukocytosis. Daptomycin was chosen out of concern for long-term linezolid toxicity and IA cultures demonstrated new linezolid resistance (Isolate 2, LVRE). After an additional three weeks of therapy, she developed a catheter-associated bloodstream infection (CLABSI). Blood cultures revealed daptomycin-resistant LVRE bacteremia (Isolate 3, DLVRE). She was started empirically on a combination of ceftaroline and daptomycin, her PICC line removed, and her blood cultures cleared. Her antibiotic course is presented in Figure 1 and resistance patterns of the VRE in Table 1.

Conclusion

In this patient, an IA abscess known to harbor VRE developed resistance to both linezolid and daptomycin during prolonged treatment with both agents. Ultimately, the patient experienced an episode of CLABSI DLVRE. Limited data exists on appropriate antibiotic choice in such challenging situations. Based on prior clinical and experimental data, we elected to use daptomycin in conjunction with ceftaroline for synergy, and the patient achieved the desired clinical response, clearance of her blood cultures and diminishing size of her IA abscess. Further work is needed to elucidate the best course of treatment for patients with VRE requiring long-term antibiotic therapy and for those who have developed extensively drug-resistant E. faecium.

Disclosures

All Authors: No reported disclosures
1255. External Validation and Systematic Quantification of the Predictive Performance of Carbapenem Resistant Enterobacterales Risk Prediction Models in Hospitalized Patients
Authors: Farkas Andras , Yassin Arsheena , Sy Hendrik , Huang Kristy , Stein Iana , Acquah Samuel , Radparvar Sara , Stavropoulos Christine , Mathew Joseph
Published: December 2021

Background

Accurately predicting the presence of a carbapenem resistant enterobacterales (CRE) in hospitalized patients presents itself as an opportunity that would support timely initiation of CRE active agents. The aim of this study is to determine how reliably the existing risk prediction models identify patients likely to require empiric anti-CRE treatment, preliminary results of which are presented herein.

Methods

A systematic search identified all existing CRE prediction models for validation in our patient population. Medical records of hospitalized patients within the Mount Sinai Health System in New York were subsequently reviewed. Data was gathered on model predictors, baseline demographics, clinical information, microbiology results, antibiotic utilization history and index infection. Besides calculating the AUROC, the main outcome of our study was to establish optimal prediction score cutoffs and false positive rates (FPR) where corresponding model performance maintains a false negative rate (FNR) of < 10%, < 20% and < 30%, respectively.

Results

12 models were retained for validation. We identified 106 patients, 41 of which were treated for a CRE infection. Previous admission, organ transplantation, CKD, infection type, and carbapenem use were baseline variables that significantly differed between the groups treated for a CRE or non-CRE related infection (Table 1). The models ability to discriminate varied as evidenced by the AUROC range of 0.5 to 0.77 (Figure 1), suggesting the Seligmen et al. model as the overall best. When evaluated at the pre-specified FNR intervals of < 10%, < 20% and < 30%, the model by Lodise et al., Seligman et al., and Vazquez-Guillamet et al. produced the best FPR, respectively (Table 2).

Table 1. Baseline characchteristics

Table 2. Model Performance

Figure 1. AUROCs

Conclusion

Discriminative ability of the risk prediction models showed varying performance. The model by Lodise et al. appears to be most useful when a low risk level is deemed acceptable for failure rate, while at a moderate to high risk of missing a CRE case (20% and 30% FNR), the methods by Seligman and Vazquez-Guillamet et al. are most desirable as they minimize the chance of over-treatment. Additional work to increase sample size and to evaluate the models inter-rater reliability is currently on going.

Disclosures

All Authors: No reported disclosures
1256. Clinical Response by Minimum Inhibitory Concentrations in Carbapenem-Resistant Pseudomonas aeruginosa Infections under Cefiderocol Compassionate Use Program
Authors: Satlin Michael J , Fam David , Echols Roger , Longshaw Christopher , Takemura Miki , Yamano Yoshinori
Published: December 2021

Background

Cefiderocol (CFDC) has been developed for the treatment of serious infections caused by drug-resistant aerobic Gram-negative pathogens, including carbapenem-resistant (CR) Pseudomonas aeruginosa (CRPA). The current CFDC susceptibility breakpoints for P. aeruginosa differ between US Food and Drug Administration (FDA) and Clinical and Laboratory Standards Institute (CLSI) (Table). Data characterizing the impact of CFDC minimum inhibitory concentrations (MICs) on the clinical responses of patients treated with CFDC for CRPA are sparse.

Methods

We reviewed patients treated with compassionate-use CFDC (2 g, q8h or renally adjusted dosages) for infections caused by CRPA with no alternative treatment options. CFDC minimum inhibitory concentrations (MICs) were evaluated according to CLSI guidelines in iron-depleted cation-adjusted Müller–Hinton broth for available CRPA isolates. We then assessed physician-reported clinical responses to CFDC therapy and stratified results by CFDC MIC.

Results

There were 71 patients overall with CRPA treated with CFDC. Treatment duration ranged from 1 to 132 days. For the subset of 33 patients for whom CFDC MIC values were available, the most common infection sites were the respiratory tract (n=15), blood (n=12), and urinary tract (n=4). Patients could have had an infection at ≥1 sites and in other locations. CFDC MIC range was ≤0.03– >64 µg/mL. The modal MIC value was 2 µg/mL (n=13; Table). CRPA isolates were susceptible to CFDC in 13/33 patients (39.4%) based on the FDA breakpoint (MIC ≤1 µg/mL) and in 31/33 patients (93.9%) based on the CLSI breakpoint (MIC ≤4 µg/mL). Clinical response was reported for 15/18 patients (83.3%) who had infections with CFDC MICs of 2–4 µg/mL, organisms that are considered susceptible by CLSI but not by FDA breakpoints (Table). Clinical response was reported in 6/13 patients (46.1%) with infections with CFDC MIC ≤1 µg/mL and in 1 of 2 patients (50.0%) with CFDC MIC ≥8 µg/mL (Table). 21 (63.6%) patients survived to Day 28 and there were no trends in mortality by CFDC MIC.

Conclusion

Clinical response rate was high for CRPA infections with CFDC MICs of 2–4 µg/mL, supporting the higher CLSI susceptibility breakpoint.

Disclosures

Michael J. Satlin, MD, MS, Achaogen (Consultant)Allergan (Research Grant or Support)BioFire Diagnostics (Research Grant or Support)Merck (Research Grant or Support)Shionogi (Consultant) David Fam, PharmD, Shionogi (Employee) Roger Echols, MD, Shionogi (Consultant) Christopher Longshaw, PhD, Shionogi (Employee) Miki Takemura, MS, SHIONOGI & CO., LTD. (Employee) Yoshinori Yamano, PhD, Shionogi (Employee)
1260. In Vitro Activity of Eravacycline Against Clinically Significant Bacteria Isolated from Patients with Cancer
Authors: Gerges Bahgat , Prince Randal , Rosenblatt Joel , Reitzel Ruth A , Shelbume Samuel , Aitken Samuel L , Aitken Samuel L , Raad Issam I , Rolston Kenneth
Published: December 2021

Background

Bacterial infections are common in patients with cancer (PWC). Many bacteria have developed resistance to currently used antibiotics, posing therapeutic challenges. we evaluated the in vitro activity of eravacycline (a novel fluorocycline) against clinical bacteria recently (2018-2019) isolated from PWC.

Methods

All 565 isolates tested were from blood cultures. CLSI approved broth microdilution method was used. Appropriate ATCC controls were included. MIC50, MIC90, MIC ranges and percent susceptibility calculations were made using FDA breakpoints when available. Eravacycline susceptibility breakpoint for most Gram-positive organisms (GPO) is ≤ 0.06 mg/L and for Enterobacterales is ≤ 0.5 mg/L.

Results

Eravacycline had potent activity against Staphylococcus aureus (methicillin-susceptible and resistant strains), oxacillin-susceptible coagulase-negative staphylococci (CoNS) including Staphylococcus lugdunensis, viridans group streptococci, beta-hemolytic streptococci. Streptococcus pneumoniae. Bacillus spp., Corynebacterium spp., and Micrococcus spp. It was slightly less active against oxacillin-resistant CoNS, and vancomycin-susceptible Enterococcus faecalis (MIC90 0,125 mg/L respectively) and was moderately active against vancomycin-resistant Enterococcus faecium (MIC50, 0.06, and MIC90. 0.25 mg/L). Eravacycline had potent activity against Escherichia coli (including ESBL producing strains), Citrobacter spp., and non-ESBL Klebsiella spp. Eravacycline inhibited 83% of ESBL positive K. pneumoniae, 83% of Enterobacter cloacae, and 80% of carbapenem-resistant Enterobacteriaceae (CRE) isolates at ≤ 0.5 mg/L. The presence of ESBLs increased MIC90 value no more than 2 fold. Eravacycline was also active against many non-fermentative GNB (Achromobacter spp., Acinetobacter spp., Sphingomonas paucimobilis, and Stenotrophomonas maltophilia).

Table 1. Percent Susceptibility of Gram-negative isolates to Eravacycline

Table 2. Percent Susceptibility of Gram-positive isolates to Eravacycline

Conclusion

Our data demonstrate that eravacycline has promising activity against clinically significant bacterial pathogens isolated from PWC including many drug resistant strains such as CRE and non--fermentative GNB. it might play an important role in the treatment of bacterial infections in PWC and warrants clinical evolution in this setting.

Disclosures

Samuel L. Aitken, PharmD, MPH, BCIDP, Melinta Therapeutoics (Individual(s) Involved: Self): Consultant, Grant/Research Support Kenneth Rolston, MD, Tetraphase Pharmaceuticals (Grant/Research Support)
1262. Salvage Therapies for Carbapenem Resistant Acinetobacter baumanii Outbreak in a Tertiary Care Center
Authors: Lai Lauren , Rose Lucia , king Madeline , Fraimow Henry , Byrne Dana D
Published: December 2021

Background

The 2019 Antimicrobial Resistance Threat Report cites carbapenem-resistant Acinetobacter baumanii (CRAB) as an urgent threat causing > 700 deaths per year.1 Acinetobacter is unique in its ability to acquire resistance determinants and pan-resistant strains have been previously reported.2 It has the propensity to cause outbreaks, especially in critically ill populations due to its ability to survive on surfaces.3,4 In 2018, our hospital experienced a large CRAB outbreak. All strains were multi-drug resistant and most were identified by the Centers for Disease Control as containing OXA-23 ß-lactamase. Standard of care (SOC) was limited to agents with high toxicity potential, and thus we explored emerging therapies. In collaboration with Shionogi Inc., we obtained compassionate use cefiderocol as salvage therapy in patients failing SOC. We present our experience utilizing various treatments for CRAB infections during a hospital outbreak.

Methods

We performed a retrospective chart review in adult patients with a CRAB infection treated with either cefiderocol or SOC for greater than 2 days from 08/2017 - 01/2020. SOC included use > 1 of the following: tigecycline, meropenem, polymyxins, amikacin, or eravacycline. At the time of our outbreak, we developed an institutional algorithm delineating which therapy to initiate depending on infection type. Demographic characteristics, illness severity scores, type of infection, and patient outcomes were evaluated.

Results

The median age [IQR] for the cefiderocol group was 57.5 [42 to 69] versus 60 [50 to 65] in the SOC group. Illness severity scores were lower in the cefiderocol group: SOFA median value [IQR] 3.5 [1.5 - 5] versus 5 [2 - 7] and CCI median value [IQR] was 3 [2.00 -3.00] versus 3 [2 -5] (Table 1). In hospital mortality was similar in both groups with the cefiderocol group having 50% in hospital mortality versus 42.2% in the SOC group. 28-day mortality was 62.6% in the cefiderocol group versus 42.4% in the SOC group (Table 2).

Conclusion

Cefiderocol may be a viable option for salvage therapy for CRAB infection. Our cohort illustrated similar outcomes as standard therapy. This study is limited by a small sample size receiving cefiderocol and the significant delay associated with obtaining cefiderocol at the time.

Disclosures

Lucia Rose, PharmD, Allergan (Speaker’s Bureau)Paratek (Employee) Madeline king, PharmD, Tetraphase (Speaker’s Bureau) Henry Fraimow, MD, Astellas pharma (Grant/Research Support)Merck (Grant/Research Support)Shionogi (Consultant, Grant/Research Support, Scientific Research Study Investigator) Dana D. Byrne, MD, MSc, Merck (Employee)
1263. In Vitro Activity of Ceftazidime-avibactam and Comparator Agents against Enterobacterales and Pseudomonas aeruginosa Collected from Patients with Bloodstream Infections as Part of the ATLAS Global Surveillance Program, 2017-2019
Authors: Lob Sibylle , Hackel Meredith , Stone Gregory , Sahm Daniel F
Published: December 2021

Background

Avibactam (AVI) is a β-lactamase inhibitor with potent inhibitory activity against Class A, Class C, and some Class D serine β-lactamases. The combination of ceftazidime (CAZ) with AVI has been approved in Europe and in the United States for several indications. This study evaluated the in vitro activity of CAZ-AVI and comparators against Enterobacterales (Eba) and Pseudomonas aeruginosa (Pae) isolates collected from patients with bloodstream infections as part of the ATLAS surveillance program in 2017-2019.

Methods

A total of 48193 Eba and 15376 Pae non-duplicate clinically significant isolates, including 9224 Eba and 1808 Pae isolated from bloodstream infections, were collected in 53 countries in Europe, Latin America, Asia/Pacific (excluding mainland China), and the Middle East/Africa region. Susceptibility testing was performed by CLSI broth microdilution. CAZ-AVI was tested at a fixed concentration of 4 µg/ml AVI. Meropenem-nonsusceptible (MEM-NS) Eba and Pae isolates were screened for the presence of β-lactamase genes.

Results

Susceptibility data are shown in the Table. Percentages of susceptibility (% S) to the tested agents were 0.4-3.4% lower among Eba and Pae from bloodstream infections compared to isolates from combined sources in most cases. CAZ-AVI showed potent in vitro activity against all Eba bloodstream isolates and the CAZ-NS subset (MIC90, 0.5-4 µg/ml, 91.7-97.4% S). Reduced activity against MEM-NS Eba was attributable to carriage of class B metallo-β-lactamases (MBLs) as 98.1% of MEM-NS MBL-negative isolates were susceptible to CAZ-AVI. None of the tested comparators exceeded the activity of CAZ-AVI. CAZ-AVI also showed good in vitro activity against the majority of Pae bloodstream isolates (MIC90, 16 µg/ml, 89.7% S). Activity was reduced against CAZ-NS and MEM-NS subsets (55.9-63.0% S), which included isolates carrying MBLs, but exceeded the activity of CAZ against MEM-NS and MEM against CAZ-NS by 26-28 percentage points. Amikacin was the only tested comparator that demonstrated comparable activity against Pae bloodstream isolates.

Results Table

Conclusion

CAZ-AVI provides a valuable therapeutic option for treating bloodstream infections caused by MBL-negative Eba and Pae isolates.

Disclosures

Sibylle Lob, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Meredith Hackel, PhD MPH, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Gregory Stone, PhD, AztraZeneca (Shareholder, Former Employee)Pfizer, Inc. (Employee) Daniel F. Sahm, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor)
1264. 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 2016-2019
Authors: Kazmierczak Krystyna , Lob Sibylle , Stone Gregory , Sahm Daniel F
Published: December 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

6654 non-duplicate isolates were collected in 52 countries in Europe (n=3423), Latin America (n=1323), Middle East/Africa (n=1177), and Asia/Pacific (excluding China; n=731) from patients (newborn to 17 y) with lower respiratory tract (LRTI; n=1687), urinary tract (UTI; n=1631), bloodstream (BSI; n=1149), skin and soft tissue (SSTI; n=1122), and intra-abdominal (IAI; n=981) infections. Susceptibility testing was performed by CLSI broth microdilution and values were interpreted using CLSI 2021 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 (97.8% susceptible (S)) and Psa (92.1% S) collected globally from pediatric patients (Table). Percentages of susceptibility to CAZ-AVI ranged from 95.4-99.2% among CA Ent from different infection types and were reduced 0.6-1.3% among HA isolates from LRTI, UTI, SSTI, and IAI. Susceptibility to CAZ-AVI was also similar (92.6-95.8% S) among CA Psa from different infection types and was reduced 1.2-7.0% among HA isolates. Larger differences in susceptibility were typically seen for the tested comparator β-lactams. For Ent, the lowest percentages of susceptibility to the tested β-lactams were observed among isolates from BSI, while the pattern was less clear for Psa.

Results 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. (Independent Contractor) Sibylle Lob, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Gregory Stone, PhD, AztraZeneca (Shareholder, Former Employee)Pfizer, Inc. (Employee) Daniel F. Sahm, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor)
1265. In Vitro Activity of Aztreonam-Avibactam against Klebsiella pneumoniae Isolates Analyzed by Epidemic Lineage and Hypervirulence Factors Collected in China as Part of the ATLAS Global Surveillance Study in 2019
Authors: Estabrook Mark , Kazmierczak Krystyna , Arhin Francis , Sahm Daniel F
Published: December 2021

Background

Hypervirulent Klebsiella pneumoniae (hvKp), unlike classical K. pneumoniae (cKp), are often responsible for community-acquired infections in otherwise healthy individuals. The acquisition of hypervirulence genes by sequence type 11 (ST11) carbapenem-resistant (CR) Kp endemic in Asia is a grave threat. Aztreonam-avibactam (ATM-AVI) is a monobactam combined with a β-lactamase inhibitor for the treatment of infections caused by Enterobacterales isolates that carry Class A, B, C and some Class D β-lactamases.

Methods

487 K. pneumoniae isolates were collected from 17 sites in China in 2019 as a part of the ATLAS global surveillance study. 220 isolates with MICs >1 µg/ml to meropenem (MEM), ceftazidime or ATM were selected for whole genome sequencing (Illumina Hiseq 2x150 bp reads). Analyses were carried out using the CLC Genomics Workbench (Qiagen). Presence of the aerobactin synthesis locus differentiated hvKp and cKp. Antimicrobial susceptibility was determined by CLSI broth microdilution.

Results

Of the 487 isolates, MIC90 values for ATM-AVI (0.5 µg/ml; Table) were lower than those for any comparator tested, with only two isolates testing with MIC >4 µg/ml. Of the isolates sequenced, 82/220 (37.3%) were ST11. 53/82 (64.6%) of these ST11 isolates were hvKp (ATM-AVI, MIC90 1 µg/ml; range, 0.25-4 µg/ml) and showed percentages of susceptibility < 90% to three last-line agents (0% MEM-susceptible (S); 18.9% amikacin (AMK)-S; 88.7% tigecycline (TGC)-S). Isolates of other STs (Non-ST11) were less frequently identified as hvKp (24/138, 17.4%) and more Non-ST-11 hvKp and cKp alike were S to MEM and AMK relative to isolates of ST11 (75.0-86.8% MEM-S; 83.3-96.5% AMK-S). Likewise, the ATM-AVI MIC90 value (0.25 µg/ml) was 4-fold lower for Non-ST11 isolates.

Results Table

Conclusion

CR ST11 hvKp represented at least 10.9% of the collected Kp isolates. ATM-AVI retained potent in vitro activity against these isolates which displayed resistance to a range of last-line agents. CST and TGC also displayed some activity but are limited in utility due to nephrotoxicity and poor accumulation in blood, respectively. The spread of virulence factors leading to the complicated clinical presentation of hvKp infection into multidrug-resistant lineages warrants continued surveillance.

Disclosures

Mark Estabrook, 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)