bluuebunny/crossref_metadata_2025_split huggingface dataset:
2533. Cerebrospinal Fluid Penetration of Cefazolin and Flucloxacillin in Children
Authors: Boast Alison , Lei Alice , Harwood Kiera , Gonis Gena , Di Carlo Amanda , Daley Andrew J , Ungerer Jacobus , McWhinney Brett , Curtis Nigel , Gwee Amanda 
Published: November 2023

Abstract

Background
Effective treatment of methicillin-susceptible Staphylococcus aureus meningitis requires antimicrobial penetration into the CSF. Anti-staphylococcal penicillins, including flucloxacillin, are generally recommended as first-line treatment. However, some evidence suggests that the first-generation cephalosporin, cefazolin, may be an appropriate alternative. We investigated the CSF concentration of cefazolin and flucloxacillin in children.

Methods
CSF samples from children aged 0-18 years treated with cefazolin or flucloxacillin were collected when there was sample remaining after diagnostic tests were completed. Unbound antibiotic concentrations of cefazolin and flucloxacillin were measured.

Results
Overall, 222 CSF samples were collected from 163 children, median age 12 months (range 0.0-17.5 years). Of these, 157 were collected while the antibiotic was at steady state. For cefazolin, children ≤1 year had a higher median CSF concentration compared with those &gt;1 year (1.8 versus 0.5 mg/L, p&lt; 0.001), whereas for flucloxacillin the concentration was similar between the two age groups (0.2 versus 0.1 mg/L, p=0.9). In infants aged ≥ 1 month to 1 year, the CSF concentration of both antibiotics was higher in those with pleocytosis (WCC &gt;5 x106/L) than those without (flucloxacillin 0.2 versus 0.065 mg/L, cefazolin 5.6 versus 1.06 mg/L). Notably, only those aged ≤1 year receiving cefazolin (7/12; 58%) achieved steady state CSF concentrations above the CLSI breakpoint for sensitive S. aureus (MIC ≤2 mg/L).

Conclusion
CSF penetration of cefazolin was higher in younger infants and for both antibiotics was higher in those with pleocytosis. In most children, the CSF concentrations in the CSF for either cefazolin or flucloxacillin were not above the S. aureus MIC.

Disclosures
All Authors: No reported disclosures
2536. Comparing the activity of broad-spectrum beta-lactams in combination with aminoglycosides and aztreonam/avibactam against 8 VIM-producing CRE
Authors: Clark Justin A , Burgess David 
Published: November 2023

Abstract

Background
Treatment of infections caused by CRE often involves beta-lactam-containing combination therapy, either with a beta-lactamase inhibitor or an agent from a different antimicrobial class. We sought to investigate the activity of several beta-lactam combinations against 8 VIM-producing CRE cultured from patients at our academic medical center using a time-kill assay.

Methods
Broth microdilution was utilized to obtain the MICs. TK was performed in duplicate with samples taken 0, 4, 8, and 24 hours after initial inoculation. During each time point, samples were automatically spiral plated onto Mueller Hinton agar plates and incubated for 16-24 hours at 37 oC before colonies were enumerated to estimate bacterial density (CFU/mL). Antimicrobials tested included meropenem 16 μg/mL, cefepime 32 μg/mL, piperacillin/tazobactam 64/4 μg/mL, amikacin 4 μg/mL, plazomicin 4 μg/mL, and aztreonam/avibactam 32/4 μg/mL. Average bacterial density reduction after 24 hours was the outcome of interest.

Results
Meropenem and plazomicin alone achieved bactericidal or bacteriostatic activity in at least a single time-kill experiment for all isolates except for meropenem against one isolate. Aztreonam/avibactam and meropenem with either amikacin or plazomicin achieved bactericidal activity by 4 hours which sustained until 24 hours except for a single isolate in which meropenem/plazomicin only achieved bacteriostatic activity. These combinations were the most active with average bacterial density decreases of 3.86, 3.89, and 3.64 log10reductions, respectively. Cefepime or piperacillin/tazobactam combined with plazomicin minimally improved the average bacterial inocula reduction compared to plazomicin monotherapy. When combined with amikacin, cefepime and piperacillin/tazobactam achieved inconsistent bactericidal activity after 24 hours, though cefepime on average led to a bacterial reduction &gt; 2 log10 CFU/mL lower than piperacillin/tazobactam.

Conclusion
Against 8 clinical VIM-producing K. pneumoniae and E. cloacae, beta-lactam combination therapy achieved rapid and sustained bactericidal activity. Further investigation is necessary to rationally guide the use of these combination therapies against CRE.

Disclosures
All Authors: No reported disclosures
2538. The Impact of Rifampicin on Blood Pressure in Patients Receiving Nifedipine: A Retrospective Study
Authors: Eljaaly Khalid 
Published: November 2023

Abstract

Background
No comparative study has been published to date to evaluate the impact of drug-drug interaction (DDI) between rifampin (CYP3A4 inducer) and nifedipine on clinical outcomes. The aim of this study was to investigate the change in systolic blood pressure (SBP) after rifampin initiation in hypertensive patients who were receiving oral nifedipine.

Methods
This retrospective cohort study was conducted at King Abdulaziz University Hospital. We included hospitalized adults ≥18 years who were started on rifampin while they were receiving oral nifedipine for hypertension. Patients with uncontrolled hypertension (baseline SBP of &gt;140 mmHg) and those receiving beta-blockers were excluded. The study outcomes were SBP changes by day 8 after rifampin initiation, which were compared by Chi-squared test.

Results
A total of 16 patients were included. The median maximum increase in SBP from baseline after starting rifampin was 24 [17.75 - 29] mmHg. The median SBP did not increase significantly on the second day (135 [128.5-141.5]; P=0.147) but the increases were significant on the following days. The median SBP was 146.5 [140.5-154.25] (P=0.002) on the third day, 142.5 [132.75-160.5] (P=0.009) on the fourth day, 149.5 [136-159.75] (P=0.005) on the fifth day, 146.5 [134.25-159.5] (P=0.012) on the sixth day, 149 [143.25-154.5] (P=0.007) on the seventh day, 151.5 [143.75-163] (P=0.007) on the eighth day.

Conclusion
Initiation of rifampin in hypertensive nifedipine-treated patients was associated with a statistically and clinically significant increase in SBP starting from day 3 of rifampin. This supports the need to avoid nifedipine use in patients taking rifampin.

Disclosures
Khalid Eljaaly, PharmD, MS, BCPS, BCIDP, FCCP, Reckitt Benckiser Healthcare International Ltd, UK: Member of the Global Respiratory Infection Partnership, supported by unrestricted educational grant from Reckitt Benckiser Healthcare Ltd
2547. Targeting penicillin-binding protein 2 (PBP2) to treat metallo-beta-lactamase (MBL)-producing Klebsiella pneumoniae: Mecillinam as an American Ninja Warrior
Authors: Klem Jack F , Candidate Pharm D , Kaur Jan Naseer , Smith Nicholas M , Chen Al , Holden Patricia N , Bulitta Jürgen B , Tsuji Brian T 
Published: November 2023

Abstract

Background
‘Nightmare’ MBL gram-negatives resistant to nearly all antibiotics have emerged in the clinical setting and are a cause for concern. Here, we assessed the role of targeted PBP2 binding using mecillinam (MEC), which is currently available in other countries and has high affinity for PBP2, as an adjuvant to established β-lactam regimens to combat pan drug resistance.

Methods
Klebsiella pneumoniae harboring blaNDM-1, blaCMY-6, blaCTX-M-15, and blaSHV-2 was exposed to an array of therapeutic drug regimens in a Hollow Fiber Infection Model (HFIM) at a starting inoculum of ∼107 CFU/mL over 168h. These arms included MEC monotherapy (2hPI Q8H, target Cmax,ss = 32 ug/mL) in addition to combination regimens that contained aztreonam (ATM) (2g 2hPI Q8H) + ceftazidime/avibactam (CAZ/AVI) (2g/0.5g 2hPI Q8H) ± MEC (2hPI Q8H, target Cmax,ss = 32 ug/mL). All drugs were discontinued at 168h, after which populations were assessed for regrowth for 48h. Samples were also collected, fixed, and imaged under a scanning electron microscope (SEM, Carl Zeiss Auriga).

Results
The MEC monotherapy arm regrew to carrying capacity (∼1010 CFU/mL) in 24h whereas combination arms demonstrated bactericidal activity throughout the duration of drug treatment. While 24h killing rates were comparable between the two combination arms, 168h counts were ∼3.0 log10 CFU/mL lower in ATM + CAZ/AVI + MEC than in ATM + CAZ/AVI (102.90 CFU/mL vs. 105.92 CFU/mL, respectively). Both combination arms recovered following drug discontinuation; however, this recovery was delayed in ATM + CAZ/AVI + MEC as was supported by a ∼6.5 log10 CFU/mL difference in 192h counts (109.51 CFU/mL in ATM + CAZ/AVI vs. 102.98 CFU/mL in ATM + CAZ/AVI + MEC). 192h SEMs supported this observation as rods predominated in the ATM + CAZ/AVI sample whereas more debris/fewer cells were apparent in the ATM + CAZ/AVI + MEC sample. Spheroplasts were observed throughout drug treatment in all samples treated with MEC.

Conclusion
The targeted PBP2 binding capacity of MEC may be a promising adjuvant to β-lactam/β-lactamase inhibitor combinations. Non-traditional β-lactam strategies that enhance the existing antibiotics may be of paramount importance for clinicians to combat MBL gram negative pan drug resistance.

Disclosures
All Authors: No reported disclosures
2548. Pharmacokinetic Analysis of Co-Administering Doravirine, Tenofovir Disoproxil Fumarate, Estradiol, and Spironolactone
Authors: Lam Kevin , Zhan Tingting , Kraft Walter , Lam Edwin 
Published: November 2023

Abstract

Background
Despite the availability of doravirine (DOR) as a fixed-dose combination product and its favorable safety profile, transgender women (TGW) are less likely to adhere to antiretroviral therapy over concerns of drug interactions with feminizing hormone therapy. This study evaluated the effect of DOR (given as a single dose containing lamivudine (3TC) and tenofovir disoproxil fumarate (TDF)) and TDF on the pharmacokinetics (PK) of estradiol (E2) and spironolactone and vice versa.

Methods
A phase I, three-period crossover, bi-directional drug interaction study was conducted. Healthy volunteers self-identified as TGW were randomized 1:1 into 2 sequences containing treatment A (DOR/3TC/TDF 100 mg/300 mg/300 mg as a single dose), treatment B (E2 4 mg twice daily, spironolactone 200 mg twice daily, and placebo for one day), and treatment C (single dose of DOR/3TC/TDF 100 mg/300 mg/300 mg, E2 4 mg twice daily, and spironolactone 200 mg twice daily for one day). Plasma DOR, TDF, E2, and testosterone were collected for PK evaluation. DOR, TDF, and E2 PK parameters were computed via a non-compartmental analysis and compared using a paired student’s t-test. Safety and tolerability were evaluated throughout the study.
Study Flow

Results
Out of 8 participants enrolled in the study, 6 completed the study. Geometric mean ratios (co-administration vs. without co-administration) and 90% confidence intervals for DOR, TDF, and E2 area under the concentration-time curve from zero to last measured concentration (AUC0-last), maximum concentration (Cmax), and concentration at 24 hours (C24) are reported in Table 1. Log-transformed DOR, TDF, and E2 PK parameters computed with and without co-administration were not statistically significant (p &gt; 0.05).
Statistical Analysis of PK Parameters for Doravirine, Tenofovir Disoproxil Fumarate, and Estradiol

Conclusion
These results demonstrate that a clinically significant interaction is not observed involving the use of feminizing hormones on DOR/TDF PK. Similarly, no observed impact on estradiol PK and testosterone is anticipated following use of DOR/TDF/3TC. DOR/TDF administered with and without E2 and spironolactone was generally well tolerated.
This work was supported by an Investigator Studies Program grant provided by Merck & Co., Inc. MISP59198. The opinions expressed are those of the authors and do not necessarily represent those of Merck & Co., Inc.

Disclosures
All Authors: No reported disclosures
2554. What’s Weight Got to Do with It? Prospective Pharmacokinetic/Pharmacodynamic Evaluation of Fixed-Dose Daptomycin
Authors: Olney Katie B , Thomas Jenni , Pai Manjunath P , Burgess Donna R , Olney William , Bruning Rebecca , Griffith Kamron Amir , Casaus Danielle , Crance Elizabeth , Burgess David 
Published: November 2023

Abstract

Background
As daptomycin (DAP) CL does not scale proportionally with weight, fixed-dose DAP has been proposed to optimize efficacy and mitigate toxicity. This study evaluated systemic exposure of a fixed dose (750 mg) of DAP in patients with Staphylococcus aureus infections.

Methods
Adult non-ICU patients with CrCl ≥ 30 mL/min admitted to our academic medical center warranting DAP for a S. aureus infection were eligible for enrollment. DAP 750 mg was infused over 30 minutes every 24 hours. At steady state, concentrations were obtained pre-dose (0.5 hours) and 1, 12, and 24 hours after the start of infusion. Concentrations were measured using a validated LC-MS assay. Pharmacokinetic (PK) analysis was performed using first-order equations and stratified by weight: low (&lt; 65 kg), normal (65-85 kg), and high ( &gt; 85 kg). Therapeutic AUC24 (≥ 666 mg*hr/L) and elevated trough (Cmin &gt; 24.3 mg/L) were the efficacy and safety targets, respectively.

Results
Overall, 22 patients (6 low weight, 8 normal weight, 8 high weight) were enrolled with no differences observed in baseline characteristics (median [IQR] age 49 [42.2, 56.5], CrCl 111 mL/min [79, 134]). PK parameters (median [IQR]) did not differ by weight with Vd 9.9 L [6.3, 17.2], Ke 0.078 h-1 [0.046, 0.098], CL 0.87 L/h [0.47, 1.34], AUC24 861 mg*hr/L [538, 1541], and Cmin 10.5 mg/L [7.3, 29.9]. Therapeutic AUC24 was achieved in 14/22 (64%) and elevated Cmin occurred in 7/22 (32%), with no differences seen among weight groups. However, differences were noted between males (n=10) and females (n=12) with significantly higher CL (median [IQR]) noted in males (1.26 L/h [0.92, 1.48]) vs. females (0.49 L/h [0.37, 0.86]) (p=0.027). Hence, median [IQR] AUC24 was significantly lower in males at 594 mg*hr/L [454, 736] vs. 1513 mg*hr/L [856, 1879] in females (p=0.021). Therapeutic AUC24 was achieved in 40% of males versus 83% of females, while elevated Cmin was seen in 20% of males and 32% of females.

Conclusion
DAP PK and exposure (AUC24 and Cmin) was not impacted by weight. These results support fixed, rather than weight-based, dosing of DAP in non-ICU patients with normal renal function. Notably, gender differences were observed with males having significantly higher CL, likely warranting higher doses of DAP to ensure optimal exposure.

Disclosures
Katie B. Olney, PharmD, BCIDP, The Society of Infectious Diseases Pharmacists (SIDP): Grant/Research Support
2558. Association of Vancomycin-Induced Acute Kidney Injury with Trough Versus AUC Monitoring in Patients Receiving Extended Durations of Therapy
Authors: Pitcock C Tyler , Wallace Katie L , Schadler Aric , Burgess David , Burgess Donna R , Cotner Sarah , VanHoose Jeremy , Gregory Eric 
Published: November 2023

Abstract

Background
Vancomycin (VAN) therapy is associated with an increased risk of AKI. Previous studies suggest that AUC monitoring reduces the risk of AKI, but literature is lacking in patients receiving longer durations of VAN therapy. This study assessed the clinical impact of AUC monitoring on patients receiving at least 14 days of VAN.

Methods
Adult inpatients at our academic medical center that received ≥ 14 days of VAN with levels obtained during a 4-year period were included in this analysis. Our primary outcome was the incidence of AKI between trough monitoring and AUC monitoring groups using the KDIGO change in serum creatinine from baseline criteria. Secondary outcomes included inpatient mortality, inpatient LOS, and ICU LOS. Multivariable logistic regression models were performed for AKI incidence and inpatient mortality.

Results
A total of 582 patients were included. The majority of patients were male (58.2%) and Caucasian (94.3%). The median duration of VAN therapy was 23 days (IQR, 16-39). Patients within the trough monitoring group had a higher incidence of AKI compared to the AUC monitoring group (45.6% vs. 28.4%, p&lt; 0.001). In each KDIGO stage, there was a higher incidence of AKI in the trough monitoring group compared to the AUC monitoring group (Stage 1: 22.0% vs. 15.9%, Stage 2: 10.7% vs. 7.6%, and Stage 3: 12.9% vs. 4.9%, p&lt; 0.001). Logistic regression analysis showed AUC monitoring was associated with a 54% lower incidence of AKI (OR 0.46, 95% CI [0.31-0.69]). ICU LOS within the trough monitoring group was longer compared to the AUC monitoring group (13 days [6-24] vs. 10 days [3-19], p=0.008). All-cause inpatient mortality was numerically higher in the trough monitoring group (12.9% vs. 8.3%, p=0.078). In the second multivariable regression analysis, AUC monitoring was not a significant predictor of mortality, but patients with AKI were five times more likely to die (OR 5.00, 95% CI [2.40-10.46], p&lt; 0.001).

Conclusion
AUC monitoring can reduce the risk of AKI in patients receiving ≥ 14 days of VAN and indirectly reduce the risk of inpatient mortality. Consideration should be given to implementing AUC monitoring as a standard of practice.

Disclosures
All Authors: No reported disclosures
2559. Antibiotic-induced Bartter-like syndrome - A Systematic Review
Authors: Priyadarshi Megha , Paul Saurav Sekhar , Soneja Manish 
Published: November 2023

Abstract

Background
Bartter syndrome encompasses salt-losing tubulopathies characterized by hypokalemia, hypochloremic metabolic alkalosis, and hyperreninemic hyperaldosteronism with normal blood pressure. Acquired Bartter or Bartter-like syndrome (BLS) is commonly associated with the use of diuretics and antibiotics such as capreomycin, netilmicin, colistin, and amphotericin B. This systematic review was done to understand the time of occurrence of Bartter syndrome post-inciting drug and gain knowledge regarding its progression and management.

Methods
We searched PubMed, Google Scholar, Embase, medRxiv, and bioRxiv databases for articles published from 1986 to March 2022 using the keywords "Antibiotic," "Bartter Syndrome," "Pseudobartter Syndrome," and "Bartter-like." Studies that reported cases of BLS in adults or children with confirmation of the inciting drug were included. We excluded studies that did not provide sufficient details of the clinical presentation and outcome.

Results
We identified 31 studies, comprising 43 cases of BLS. The mean age of the patients was 41.1 years (range: 25–57 years), and 65.1% were female. The most common antimicrobial class associated with BLS was aminoglycosides (65.1%), followed by the polymyxin group. The most common antimicrobial was Gentamicin (41.8%), followed by Colistin (32.5%), Streptomycin, and Capreomycin (6.9% each). Hypokalemia(100%), metabolic alkalosis(97.2%), hypocalcemia(92.5%), and hypomagnesemia(100%) were reported in almost all patients. The median time of onset after exposure to the inciting agent was 10 days (range 7–18 days), and the median time for resolution after stopping the drug was 14 days (range 7–31 days). There was a complete resolution of the symptoms following discontinuation in all cases.
Demographic and baseline characteristics of the patients

Prevalence of electrolyte, acid-base disorder, and urinary electrolyte abnormalities
Laboratory parameters among the reported cases

Conclusion
BLS is a rare but potentially reversible complication of various antimicrobials, most commonly aminoglycosides. The diagnosis requires a high index of suspicion and a careful review of the drug history. The prognosis is favorable, with a complete reversal of the state after drug discontinuation.

Disclosures
All Authors: No reported disclosures
145. Tracheal Aspirate Order Indications and Associated Culture Results in Mechanically Ventilated Children
Authors: Jelic Monika , Weber Matthew J , Birkholz Meghan C , Dowell Elaine , Hamilton Stacey , Jung Sarah A , Baker Christopher D , Parker Sarah K , Dominguez Samuel R 
Published: November 2023

Abstract

Background
Tracheal aspirates (TAs) are collected on mechanically ventilated patients to aid in diagnosis of tracheitis or ventilator associated pneumonia. Accuracy of TA cultures to diagnose lower respiratory tract infections is low, limited by normal respiratory flora contamination, making interpretation difficult. To aid diagnostic stewardship efforts, we analyzed TA order indications to better understand why TA cultures were ordered and which indications were associated with a clinically significant culture result.

Methods
Order indications for TA specimens were implemented in Sept. 2021 at Children’s Hospital Colorado. At least one indication was required at the time of order placement, Table 1. We extracted all TA orders from Sept. 2021 to Aug. 2022, as well as demographics, collection department, and Gram stain/culture results.

Results
1,439 tracheal aspirate specimens were ordered for 496 unique patients. 34% were collected in the Emergency Department (ED), 22% in the Neonatal Intensive Care Unit (NICU), and 20% in the Pediatric Intensive Care Unit (PICU; Table 1). The two most common order indications were increase in secretions (37%) and increase in ventilator support (36%). 296 (22%) cultures grew 1 or 2 predominant organisms, with the most common indication being increased secretions; 57% of these cultures grew respiratory pathogens. Overall, 42% of cultures grew normal respiratory flora and 12% had no growth. For cultures with no growth and those with no organisms on Gram stain, the most common indication was increase in ventilator support. For all order indications, 50% or more grew normal respiratory flora with abnormal chest imaging and fever having the most cultures with 1 or 2 predominant organisms.

Conclusion
The majority of TAs are collected in the ED, NICU or PICU. The most common order indications were increase in secretions or increase in ventilator support. The most common order indication that was noted in actionable cultures (1 or 2 predominant organisms) was increased secretions, though order indication was not predictive. These results have informed potential Gram stain rejection criteria to improve diagnostic yield for clinically relevant pathogen detection.

Disclosures
Sarah A. Jung, PhD, Abbott Molecular Inc: Research support|DiaSorin Molecular: Research|Karius: Advisor/Consultant|Karius: Industry talks at two conferences Samuel R. Dominguez, MD, PhD, Biofire Diagnostics: Advisor/Consultant|Biofire Diagnostics: Grant/Research Support|Cobio Diagnostics: Board Member|Karius: Advisor/Consultant|Pfizer: Grant/Research Support