bluuebunny/crossref_metadata_2025_split huggingface dataset:
1532. Population Pharmacokinetic (PPK) Modeling and Simulation of Long-Acting (LA) Cabotegravir (CAB) to Inform Strategies Following Dosing Interruptions in HIV-1-Infected Subjects
Authors: Han Kelong , Baker Mark , Patel Parul , Margolis David , Spreen William , Moore Katy P , Ford Susan L 
Published: October 2019

Abstract

Background
CAB is an integrase strand transfer inhibitor under investigation as an injectable LA formulation for the treatment and prevention of HIV, and as a tablet formulation as an oral lead-in (OLI) and bridging treatment for dose interruptions. The monthly injection regimen of CAB LA and rilpivirine (RPV) LA was noninferior to standard oral therapy in maintaining HIV-1 suppression in Phase 3 trials. PPK modeling and simulation was used to inform strategies for managing dosing interruptions.

Methods
A 2-compartment model with first-order oral and LA absorption and elimination adequately described the data from 1,647 healthy (28%) and HIV-infected (72%) adult subjects in 16 studies. Gender was a significant covariate on LA absorption; therefore, simulations of 5,000 virtual subjects were performed using a 4:1 male:female ratio to ensure 1,000 representative females and covariate sampling with replacement from the analysis dataset. One- to 12-week delays in dosing of the second, third, and fourth injection were simulated, and predicted troughs were compared with the 5th percentile (0.65 μg/mL) of trough concentrations following the first injection in Phase 3. Simulations of 1–2 months of oral bridging with CAB 30 mg once daily from time of a missed injection until CAB LA dosing resumed were performed, with the median Cmax (13.1 μg/mL) observed following oral CAB 60mg once daily in Phase 2b as an upper reference.

Results
Proportions of subjects predicted to achieve target plasma CAB trough concentrations are shown by length of delay and injection visit in Table 1. Oral bridging with CAB 30mg once daily starting at the time of a planned missed injection is predicted to provide exposures within ranges observed in clinical studies (Figure 1).

Conclusion
Dosing delays of up to one week appear to have minimal impact, but the effect is more likely to become problematic with longer delays, particularly in the first few months of dosing. Oral bridging provides therapeutic and safe exposures for planned interruptions in LA dosing. Regardless of use of oral bridging, simulations support resuming CAB LA dosing for interruptions <1 month (<2 months between injections) and reinitiating CAB LA with a loading dose and subsequent monthly injections for interruptions ≥ 1 month (≥ 2 months between injections).

Disclosures
All authors: No reported disclosures.
1535. Pharmacokinetic (PK) and Pharmacodynamic (PD) Evaluation of Cefepime (CPM) in Obese and Non-Obese Patients
Authors: Morrisette Taylor , Neville Nichole , Mueller Scott W , Britton Abbie , Jacknin Gabrielle , Miller Matthew A , Fish Douglas N 
Published: October 2019

Abstract

Background
Appropriate application of antimicrobial PK/PD properties is crucial to optimizing patient outcomes. Although β-lactams are among the most utilized and effective antibiotics, optimal dosing strategies in obese populations are largely unknown. The objective of this study was to compare PK/PD of CPM in non-obese (NO, weight 80–100 kg) and obese (O, weight > 100 kg) patients.

Methods
A prospective comparative PK/PD analysis was conducted in NO and O patients receiving CPM. Blood samples were obtained at 30, 60, 120, 240, 360, and 480 minutes after CPM infusion. CPM concentrations were determined by reversed-phase high-performance liquid chromatography. Non-compartmental PK analyses were performed, followed by Monte Carlo simulations (Oracle Crystal Ball®, 5,000 simulated patients) to estimate probability of target attainment (PTA) against common Gram-negative pathogens. The desired PD target for CPM was % time above MIC of unbound drug (%fT > MIC) ≥ 60%. Chi-squared and Mann–Whitney U tests were used for analysis.

Results
Seventeen patients were enrolled and most (94%) received CPM 2 g q8h. A significant difference in actual body weight and body mass index was observed (P < 0.001). There were no differences in other baseline or PK characteristics between the two groups. Utilizing CPM 2 g q8h, PTA ≥ 90% was not observed for organisms with an MIC of 8 μg/mL, the current CLSI breakpoint for P. aeruginosa and A. baumannii (PTA = 88% vs. 81% in NO and O groups, respectively). With a 6 g continuous infusion (CI), however, ≥ 90% PTA was achieved in both groups (PTA = 100%) for organisms with an MIC of 8 μg/mL, while a regimen of 2 g q8h (infused over 3 hours [EI]) also provided PTA of ≥ 90% in both groups (PTA = 98% vs. 92% in NO and O groups, respectively). Goal PTA was not obtained in either group for organisms with an MIC of 4 μg/mL with CPM 1 g q8h or 2 g q12h (i.e., CLSI recommended dosing for organisms with MICs of 4 μg/mL).

Conclusion
Optimizing PK/PD parameters through novel dosing strategies are essential in both the NO and O populations for optimal CPM exposure in susceptible pathogens with higher MICs. CPM 6 grams/day by either CI or EI provides more optimal PK/PD characteristics in obese patients for pathogens with MICs at or near the current CLSI-recommended breakpoint.

Disclosures
All authors: No reported disclosures.
1551. Systemic Tobramycin Absorption Resulting from Antibiotic-Impregnated Cement Spacers for the Treatment of Prosthetic Joint Infection
Authors: Como James D , Abdulmassih Rasha , Guarascio Anthony J , Sauber Timothy , Sewecke Jeffrey , Westerick Edward 
Published: October 2019

Abstract

Background
Antibiotic-impregnated cement spacer (ACS) placement has been a cornerstone of two-stage surgical management of prosthetic hip and knee infection for decades. Utilized antibiotics have included aminoglycosides and vancomycin. Pharmacokinetic modeling studies have described peak systemic levels within the first 24–48 hours post-operatively, followed by rapid clearance. While this systemic exposure was previously felt insufficient to cause organ toxicity, a few studies have described antibiotic-induced nephrotoxicity.

Methods
We prospectively enrolled patients with prosthetic hip or knee infection, and subsequent ACS placement, containing vancomycin and tobramycin, from October 2017 to February 2019, at Allegheny General Hospital. Risk factors for post-operative nephrotoxicity, including patient comorbidities, receipt of potentially nephrotoxic medications, estimated creatinine clearance (CrCl), perioperative hypotension, total spacer tobramycin dosage, and post-operative day 1 (POD1) and 3 (POD3) serum tobramycin levels were recorded. Patients who had antibiotic cement spacer exchange, or had received systemic aminoglycoside therapy, were excluded.

Results
Thirteen patients were enrolled, comprising 4 hip and 9 knee ACS, with respective median (interquartile range (IQR)) tobramycin cement dosages of 3.8 (2.86–4.58) and 4.8 (4.8–9.6) grams. Tobramycin levels were measured at a median 16.5 and 60.7 hours on POD1 and POD3, respectively. Three hip and six knee ACS had respective, detectable POD1 median serum tobramycin levels of 0.6 (0.38–1.20) and 0.8 (0–0.8) μg/mL; three knees, but no hip ACS had detectable POD3 serum tobramycin levels. Six of the nine patients with detectable POD1 serum tobramycin levels had a CrCl of less than or equal to 65 mL/minute (figure), while each patient with detectable POD3 levels had a CrCl of less than 45 mL/minute. No significant changes in baseline CrCl were identified. A relationship between tobramycin cement dosage and detectable serum tobramycin levels was not observed.

Conclusion
Low baseline CrCl, but not the total tobramycin dosage or other nephrotoxicity risk factors, may be the single most reliable predictor of detectable postoperative systemic tobramycin levels in patients who have received hip or knee ACS.

Disclosures
All authors: No reported disclosures.
1578. Rifampicin Reduces Tedizolid Concentrations When Co-Administered in Healthy Volunteers
Authors: Lee Lawrence , Hor Hee Kim , Paton Nicholas 
Published: October 2019

Abstract

Background
Tedizolid is an oxazolidinone used to treat skin and soft-tissue infections. Rifampicin is a rifamycin antibiotic which can also treat skin and soft-tissue infections, such as those caused by Staphylococcus aureus. Tedizolid and rifampicin could be therefore used concurrently to treat infections. There is currently no clinical data on whether rifampicin affects tedizolid concentrations. Rifampicin is known to be an inducer of cytochrome P450s and transporters. Tedizolid is not known to be cleared by cytochrome P450s, but could be affected by other clearance mechanisms. Therefore we conducted a pharmacokinetic drug-drug interaction study to investigate whether 2 weeks of rifampicin can affect tedizolid concentrations.

Methods
We conducted a healthy volunteer study in 8 subjects. Subjects were first given linezolid 600 mg on day 1, tedizolid 200 mg on day 4, rifampicin 600 mg daily from days 5 to 19 (2 weeks of rifampicin), and an additional dose of tedizolid 200 mg on day 19. Blood was obtained at pre-dose, 1, 2, 3, 4, 5, 6, 8, and 24 hours post dose on days 4 and 19. Concentrations of tedizolid were measured using a validated liquid chromatography / mass spectrometry method.
Pharmacokinetic parameters were calculated by Non-Compartmental Analyses using Phoenix WinNonLin version 8.0. The bioequivalence module was used to obtain ratios of PK parameters pre- and post-rifampicin.

Results
Eight subjects were included in the study. Median age (range) and weight were 34.5 (29–44) years and 64 (58.4–90.8) kg, respectively. Tedizolid was well tolerated in the study. Tedizolid AUC (0–24 hours) was reduced after 2 weeks of rifampicin (GMR 0.80, 90% confidence interval 0.73–0.88), as was Cmin (0.54, 0.44–0.66) and Cmax (0.85, 0.79–0.91). Clearance/F of tedizolid was significantly increased after rifampicin (1.35, 1.21–1.50).

Conclusion
Rifampicin given for 2 weeks has the potential to reduce tedizolid concentrations, especially trough levels, which was reduced by 46%. Caution is recommended when using tedizolid together with rifampicin, especially when tedizolid MIC is high or treating difficult infections.

Disclosures
All authors: No reported disclosures.
1593. Analysis of Hospital Antimicrobial Susceptibility Test Results for Patterns of Antibiotic Resistance
Authors: Beckley Andrew , Wright Erik S 
Published: October 2019

Abstract

Background
Antimicrobial susceptibility tests (ASTs) are routinely performed on pathogens isolated from clinical samples. ASTs are used by clinicians to select the most appropriate treatment for antibiotic-resistant microorganisms. In aggregate, ASTs offer insight into the rise and spread of antibiotic resistance across hospitals. Here, we used ASTs to identify patterns of antibiotic resistance across drugs and microorganisms.

Methods
We conducted a retrospective analysis of 364,813 AST results from the University of Pittsburgh Medical Center from 2015 to 2018. Data regarding infection site, hospital laboratory testing, organism identification, and antibiotic susceptibilities were extracted from the laboratory information system and anonymized prior to use. The pathogens studied included Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii, Staphylococcus aureus, Proteus mirabilis, and Enterococcus faecalis.

Results
We identified 21 antibiotic-pathogen combinations where resistance was found in less than 1% of AST results. Concordant susceptibility results of levofloxacin and ciprofloxacin occurred the most frequently among antibiotic pairs. Additionally, concordant susceptibility results were more common within antibiotics belonging to the same antibiotic class than between classes. P. aeruginosa had the highest rate of overall concordant results with concordance occurring within all -lactam classes. In contrast, K. pneumoniae and P. mirabilis showed the least concordance, suggesting that their resistance profiles are less predictable. Notably, we did not identify any pairs of antibiotics that strongly exhibited discordant susceptibility results regardless of the microorganism.

Conclusion
Using routinely collected clinical microbiological data, we were able to characterize pathogen-antibiotic combinations where resistance is rarely seen. Additionally, we identified pairs of antibiotics that frequently exhibited concordance susceptibilities both within and between classes. Lastly, we were unable to find evidence of discordant susceptibility results, indicating that more clinical research is needed to determine the efficacy of collateral sensitivity treatment techniques.

Disclosures
All authors: No reported disclosures.
1594. Ceftolozane–Tazobactam Demonstrates Higher In Vitro Susceptibility than Ceftazidime–Avibactam Against Pseudomonas aeruginosa Isolated from Respiratory Tract of Adult Cystic Fibrosis Patients
Authors: Nolan Patrick James , Smith Tiffeny , Finklea James D , Cohen Leah , Jain Raksha 
Published: October 2019

Abstract

Background
Pseudomonas aeruginosa is a commonly isolated pathogen in adults with cystic fibrosis (CF). Antimicrobial resistance is an escalating problem due to chronic colonization and frequent antimicrobial exposure. Ceftolozane–tazobactam (C/T) and ceftazidime–avibactam (CZA) exhibit promising activity against antimicrobial-resistant organisms, including P. aeruginosa. In this study, we compared in vitro activity of C/T and CZA against P. aeruginosa isolated from respiratory cultures obtained from adult patients with CF.

Methods
This is a retrospective study of respiratory cultures positive for P. aeruginosa collected from adult CF patients between January 1, 2015 to November 30, 2018. The first isolate per patient per year that underwent susceptibility testing for C/T, CZA, and colistin were included in the study. All isolates underwent in-house susceptibility testing for 9 anti-pseudomonal agents according to the methodology established by the Clinical Laboratory Standards Institute (CLSI). Susceptibility testing of C/T, CZA, and colistin were performed by a reference lab. Isolates were classified into 3 drug-resistant categories using the following definition: multidrug-resistant (MDR) non-susceptible (NS) to ≥1 agent in ≥3 different antimicrobial classes, extensive drug-resistant (XDR) NS to 4 or 5 different classes, and pan drug-resistant (PDR) NS to all 6 classes except colistin.

Results
Forty-two P. aeruginosa respiratory isolates from 32 patients with CF were included. The overall susceptibility to C/T and CZA was 59.5% and 42.9%, respectively. Thirty-eight (90%) isolates were considered MDR with susceptibility of 55.3% to C/T and 44.7% to CZA. Among the 11 XDR isolates, susceptibility to C/T was 81.8% vs. CZA 72.7%. Susceptibility to C/T vs. CZA was also higher (37.5% vs. 25%) among the 24 PDR isolates.

Conclusion
Among P. aeruginosa isolated from CF respiratory cultures, C/T appears to have better in vitro activity compared with CZA, and remained true among isolates considered XDR and PDR. These results suggest using C/T while awaiting susceptibilities when standard anti-pseudomonal agents cannot be used. Future studies evaluating clinical outcomes for the treatment of pulmonary CF exacerbations are needed to assess the applicability of in vitro susceptibility data.

Disclosures
All authors: No reported disclosures.
1597. Evaluation of Ceftaroline Resistance (CPT-R) in Chile Across Time and a Comparison of CLSI vs. EUCAST Breakpoints in Methicillin-Resistant Staphylococcus aureus (MRSA)
Authors: Khan Ayesha , Rivas Lina M , Spencer Maria , Martínez Jose R W , Lam Marusella , Rojas Pamela , Porte Lorena , Silva Francisco , Braun Stephanie , Valdivieso Francisco , Mϋlhauser Margareta , Lafourcade Mónica , Miller William R , Garcia Patricia , Arias Cesar A , Munita Jose M 
Published: October 2019

Abstract

Background
CPT-R in MRSA is associated with clonal complex (CC) 5 lineages. Chile, with wide dissemination of the CC5 Chilean-Cordobes clone, has high MRSA rates. In 2019, CLSI revised the breakpoints (BPs) keeping susceptible (S, minimum inhibitory concentration [MIC mg/L] ≤1), added susceptible dose-dependent (SDD, MIC 2–4), removed intermediate (MIC 2); resistant (R) is now MIC ≥8. EUCAST S is MIC ≤ 1, but R differentiates among pneumonia (MIC > 1) and nonpneumonia (NP) isolates (MIC > 2). We evaluated CPT-R across time and agreement between agencies for broth microdilution (BMD), E-test and Disk Diffusion (DD)

Methods
Hospital- (HA; n = 320, 10 centers) and community-associated (CA, n = 37) clinical MRSA isolates collected between 1999 and 2018 were confirmed with MALDI-TOF, cefoxitin DD, and mecA PCR. CPT susceptibilities were evaluated by BMD, E-test and DD (5 and 30 mg) across revised and old CLSI or EUCAST BPs. We determined essential and categorical agreement (EA, CA), very major, major, and minor errors (VME, ME, MiE)

Results
The MIC50/MIC90 of HA-MRSA with BMD was 2/2 mg/L (64% of isolates considered CPT non-susceptible) and 0.5/0.5 mg/L for CA-MRSA. MIC50/MIC90 was 1/1.5 with E-test. Strains collected in 1999–2008 (n = 161) and 2009–2018 (n = 159) both had a MIC50/MIC90 of 2/2. The EA of E-test with BMD was 82%; results of CA-VME-ME-MiE were 51-0-0-48% using the new CLSI BPs or 51-81-0-45% using EUCAST or old CLSI BPs. For BMD, CA-VME-ME-MiE between new CLSI and EUCAST was 95-0-0-5 with 100% CA for E-test. Under NP EUCAST BPs, R isolates increase from 5 to 21% by BMD and 0 to 8% by E-test. CA-VME-ME-MiE between new CLSI and NP EUCAST BPs for BMD is 79-0-0-21 and for E-test is 91-0-0-8. For DD vs. BMD, CA-VME-ME-MiE is 55-0-1-44 with new CLSI BPs, 53-63-1-43 with old CLSI and 36-6-35-51 with EUCAST. With EUCAST DD (5 μg CPT) as reference vs. CLSI DD (30ug CPT), CA-VME-ME-MiE is 25-70-0-38.

Conclusion
CPT nonsusceptibility is frequent in the CC5 HA-MRSA clone circulating in Chile across time. All methods had poor performance against BMD, but revision of CLSI BPs decreased error rates. E-test under called the MIC. CLSI DD (under called nonsusceptibility) and EUCAST DD (overcalled resistance) are drastically discordant. Respiratory isolates evaluated under NP BPs increased rates of resistance.

Disclosures
All authors: No reported disclosures.
1622. Clinical and Environmental Surveillance of Legionella pneumophila in a Tertiary Healthcare Center in India
Authors: k Sreenath , Chaudhry Rama , Ev Vinayaraj , Dey A B , Kabra S K , Guleria Randeep 
Published: October 2019

Abstract

Background
Legionellosis is a form of pneumonia caused by Gram-negative bacilli belonging to the Legionella genus. In India, sporadic cases of legionellosis have been reported, but the incidence of this infection is still believed to be underestimated. We conducted a proactive clinical–environmental surveillance in a tertiary healthcare center to determine the frequency of legionellosis, and to identify the pathogen in the hospital water systems.

Methods
During February 2015–February 2019, we enrolled 533 cases (310 males, 223 females) with a diagnosis of pneumonia; a respiratory secretion was collected from each patient and tested for L.pneumophila by using a real-time PCR targeting mip gene. To identify Legionella spp. present in hospital water systems, we collected 201 hospital water samples and were analyzed by cultivation in BCYE agar. Legionella speciation and identification of Lp1 was done by real-time PCR assay.

Results
Among 533 cases, 11(2.1%) [6 male, 5 female] tested positive for L.pneumophila by real-time PCR. Of these, all were community-acquired sporadic cases not associated with a cluster or outbreak. Risk factors including smoking, alcohol use, malignancy, underlying respiratory disease, hypertension were identified in 8 (72.7%) cases. The duration of hospitalization for Legionella patients was 8–24 days; 5/11 (45.5%) patients were admitted to intensive care units. Of 11 patients 8 (72.7%) survived, and 3(27.3%) died. Among the 201 water samples tested, 38 (18.9%) tested positive for L.pneumophila by culture. The presence of Lp1 was detected in 25 (12.4%) water samples. Legionella spp. was recurrently isolated from patient areas, cooling towers, residential areas, and other areas inside the hospital campus.

Conclusion
The study indicates a low prevalence of legionellosis in this region. Even though Legionella colonization was detected in the hospital water system, no cases of hospital-acquired legionellosis were discovered during the study period. However, considering the risk of nosocomial legionellosis to patients we formulated Legionella control strategies in this hospital. Point-of-use filters were installed to the potable water units from where Legionella was isolated and repeat sampling from these sites were found to be negative for the contagion.

Disclosures
All authors: No reported disclosures.
1625. Risk of Invasive Group A Streptococcus, Group B Streptococcus, and Streptococcus pneumoniae Infection Among Adults Experiencing Homelessness—Anchorage, Alaska, 2002–2015
Authors: Mosites Emily , Zulz Tammy , Bruden Dana , Nolen Leisha , Frick Anna , Castrodale Louisa , McLaughlin Joseph , Van Beneden Chris , Hennessy Thomas , Bruce Michael 
Published: October 2019

Abstract

Background
People experiencing homelessness (PEH) have an increased risk of infectious disease. However, for many infections, this increased risk has not been clearly quantified. For example, the risk of invasive streptococcal infection has not been established among PEH in the United States.

Methods
We compared the incidence of detected cases of invasive group A Streptococcus (GAS) infection, group B Streptococcus (GBS) infection, and Streptococcus pneumoniae (pneumococcal) infection among adult PEH to that in the general adult population in Anchorage, Alaska from 2005 through 2015 using data from the CDC Arctic Investigations Program surveillance system, the US census, and the Anchorage Point in Time count (PIT [a yearly census of PEH]).

Results
During 2005–2015, the PIT counted a mean number of 970 adults (minimum 795, maximum 1486) in Anchorage who were homeless, which accounted for 0.4% of the total population. Compared with the general population, PEH were 53 times as likely to have invasive GAS infection (95% CI 47–61), 7 times as likely to have invasive GBS infection (95% CI 6, 8), and 36 times as likely to have invasive pneumococcal infection (95% CI 33, 40). Of all invasive GAS cases in Anchorage over the time period, 19% occurred within the homeless population, while 3% of invasive GBS cases and 14% of invasive pneumococcal cases were within the homeless population. Additionally, the predominant subtypes of GAS and pneumococcus differed among PEH compared with the general population.

Conclusion
A disproportionate burden of invasive streptococcal disease in Anchorage was detected among PEH, indicating a need for further focus on this high-risk group.

Disclosures
All authors: No reported disclosures.