bluuebunny/crossref_metadata_2025 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

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

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

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

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

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

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

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

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

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.
1651. The Impact of the 2017–2018 Influenza Season on Acute Care Hospitals in the United States: A Qualitative Evaluation of Immediate Responses and Future Preparedness
Authors: Harris Gavin H , Rak Kimberly J , Kahn Jeremy M , Angus Derek C , Caplan Erin A , Mancing Olivia , Driessen Julia , Wallace David J
Published: October 2019

Background

The 2017–2018 influenza season was characterized by high illness severity, wide geographic spread, and prolonged duration compared with recent years in the United States – resulting in an increased number of emergency department evaluations and hospital admissions. The current study explored how US hospitals perceived the impact of influenza during this time period, including effects on patient volumes, ways in which hospitals responded, and how lessons learned were incorporated into future influenza preparedness.

Methods

We conducted semi-structured phone interviews with capacity management personnel in short-term acute care hospitals across the United States. A random hospital sample was created using Centers for Medicare and Medicaid Services annual reports. Hospitals self-identified key informants who were involved with throughput and capacity. The interview guide was developed and pilot tested by a team of clinicians and qualitative researchers, with interviews conducted between April 2018 and January 2019. We performed thematic content analysis to identify how hospitals experienced the 2017–2018 influenza season.

Results

We achieved thematic saturation after 53 interviews. Responses conformed to three thematic domains: impacts on staff and patient care, immediate staffing and capacity responses, and future preparedness (Table 1). Hospitals almost universally reported increased emergency department and inpatient volumes that frequently resulted in strain across the hospital. Strain was created by both increased patient volume and staff shortages due to influenza illness. As strategies to address strain, respondents reported the use of new protocols, new vaccination policies, additional staffing, suspected-influenza treatment areas, and more frequent hospital administration meetings. Many hospitals reported increased diversion time. Despite experiencing high levels of strain, some hospitals reported no changes to their future influenza preparation plans.

Conclusion

Acute care hospitals experienced significant strain as a result of the 2017–2018 influenza season. Hospitals implemented a range of immediate responses to seasonal influenza, but generally did not report future planning specific to influenza.

Disclosures

All authors: No reported disclosures.
1684. Clinical Profile and Outcome of Scrub Typhus-Related Acute Respiratory Distress Syndrome in Adults Presenting to a Tertiary Care Hospital in North India
Authors: Kumari Savita , Suri Vikas , Rao H R , Bhalla Ashish , Singh Inderpaul , Singh Mini P , Biswal Manisha , Goyal Kapil , Zaman K , Ratho R K
Published: October 2019

Background

To study the clinical profile and outcome of adult patients presenting with Scrub typhus ARDS in emergency at our institute.

Methods

Prospective observational study which included 126 adult patients presenting to emergency department at, PGIMER Chandigarh, a tertiary care referral institute in northwestern India with acute febrile illness with ARDS (acute onset respiratory distress within one week of fever or new/worsening respiratory symptoms with PaO2/FiO2 ratio less than 300 with PEEP or CPAP more than 5 cm H2O from January 2016 to December 2017.All the patients consenting for the study underwent detailed clinical evaluation and investigated for the etiology as per standard protocol followed at our institute with special emphasis to rule out tropical illnesses like scrub typhus, malaria, leptospirosis, dengue and H1N1 influenza. Patients were followed till discharge.

Results

Out of 126 patients eligible for the study, 45.2% were males and 54.8% were females. 47.6% were admitted in the monsoon/post-monsoon period. In addition to fever and dyspnea, cough (75.8%), hepatomegaly (56%), myalgia (63%), splenomegaly (31.3%), pedal edema (34.2%), pallor (40.4%), and vomiting (48.4%) were the common symptoms observed. Scrub typhus in 33.3%, followed by H1N1 influenza in 15.8%, co-infections in 12.6%, leptospirosis in (4.76%), dengue in (3.96%) and malaria in 3.17% of the patients, were the most common etiologies encountered. In 26.9% patients, no definite infective etiology could be found. Among the scrub typhus patients, 16 required ventilation. SOFA score of more than 6 was noted in 24 (57.14%) patients with scrub typhus as compared 9 (47.3%) patients with H1N1 infection. 12.1% of patients with scrub typhus succumbed to their illness when compared with 36.8% of patients with H1N1 infection. At admission in emergency female sex (P = 0.048), age less than 45 years, (P = 0.020), abdominal pain (P = 0.011), presence of hepatosplenomegaly (P = 0.001/0.010), thrombocytopenia <150,000 (P = 0.001), transaminitis (P = 0.00) were significant predictors of a diagnosis of scrub typhus when compared with a non-scrub typhus etiology of patients with fever and ARDS.

Conclusion

Scrub typhus is an important, treatable tropical infection causing ARDS especially in monsoon/post-monsoon seasons in Northwestern India.

Disclosures

All authors: No reported disclosures.
1692. Epidemiology, Clinical Characteristics, and Outcomes of Candidemia in a Tertiary Hospital in the Dominican Republic
Authors: Rojas Fermin Rita , Germosen Edwin , Mena Lora Alfredo J , Guzman Anel E , Tolari Gilda , Bleasdale Susan C
Published: October 2019

Background

Candidemia is a major cause of morbidity and mortality in hospitalized patients. The global epidemiology of invasive Candidiasis is changing, with distribution of species and resistance varying in different geographic and healthcare settings. There is a paucity of data on candidemia in the Dominican Republic (DR). Understanding epidemiologic risk factors and resistance rates may improve early diagnosis and empiric antifungal selection.

Methods

We performed a retrospective review of patients with positive Candida blood cultures from January 2017 to December 2018. Data were extracted from medical records. Clinical and demographic information, including co-morbidities, antifungal sensitivities, and outcomes were collected.

Results

A total of 52 cases were identified, 34 in 2017 and 18 in 2018. Ages ranged from <1 to 89 years and was distributed in various groups (Figure 1). The most common comorbidities included DM (38%), nephropathy (37%), cerebrovascular accident (25%), and malignancy (19%). Device use and prior antimicrobial exposure were the most common risk factors (Table 1). There was no antifungal resistance to amphotericin, voriconazole, or echinocandins. No fluconazole resistance was found in 2017, compared with 11% resistance in 2018 in C. albicans, C. glabrata, and C. tropicalis species. Mortality was 64% in 2017 and 61% in 2018.

Conclusion

Candidemia with non-albicans Candida species was common (87%). Susceptibilities and species varied by year but did not affect mortality. Resistance to fluconazole is rising but remains low and other antifungals retain susceptibility. Indwelling catheters, mechanical ventilation and antibiotic exposure were common risk factors in our cohort. Mortality for candidemia was high. Rapid diagnostic testing and early empiric therapy with echinocandins for patients at risk may curb mortality.

Disclosures

All authors: No reported disclosures.
1695. Clinical and Microbiological Characterization of Candida parapsilosis Complex Infection in a Tertiare Care Hospital from Cali, Colombia
Authors: Martinez Luisa F , Sanz Ana M , Martinez Diana M , Rosso Fernando , Parra Claudia M
Published: October 2019

Background

Candidemia and invasive candidiasis are major causes of morbidity and mortality among critically ill patients and neonates. Every year more than 250,000 people develop invasive candidiasis, causing more than 50,000 deaths worldwide. Candida albicans is the most frequently isolated species worldwide. However, species distribution, epidemiology, and resistance have changed. C. parapsilosis complex (CPC), which has a global rate of fluconazole (FCZ) resistance range between 2 and 5% and has been related to echinocandins resistance, is the second most isolated species at Fundación Valle del Lili (FVL). We aim to describe the clinical and microbiological characteristics of fungal infections by C. parapsilosis, and determine FCZ resistance rates.

Methods

An observational prospective study was conducted. The study included patients with CPC isolations attended at FVL from 2016 to 2017. The strains were identified by mass spectrometry (MALDI TOF® Bruker, Biotyper 3.1). Minimal inhibitory concentrations (MIC) were determined by broth microdilution (M27 A3 CLSI). Statistical univariate analysis was performed; Differences between resistant cases and nonresistant cases were assessed through U Mann–Whitney test, Pearson chi-squared test or Fisher exact test.

Results

55 patients had CPC isolations during the study period: 18 newborns, 13 children, and 24 adults. Most isolations were from blood cultures (n = 31) (14 of them newborns), bronchoalveolar lavage (n = 9), peritoneal fluid (n = 8), and catheter tips (n = 3). The resistance was 36%. 52 strains were C. parapsilosis ss, of them, 20 were FCZ resistant; 3 strains were C. orthopsilosis, all of them FCZ sensitive. The MIC50 = 1 µg/mL and MIC90 = 16 µ/mL. Patients with previous antifungal treatment had a higher risk of FCZ resistance (RR: 2.14, 95% IC 1.07–4.26). The mortality brute rate was 30%, patients with diabetes and renal failure death risk (RR: 3.1, 95% CI: 1.4 – 6.9) and (RR: 2.96, 95% CI: 1.4 – 6.4), respectively. Candidemia was present in 50% of deaths among children with parenteral nutrition.

Conclusion

Fluconazole resistance in CPC has increased in the last decade. Newborns receiving parenteral nutrition had a higher proportion of CPC fungemia; we also found higher mortality rates among this population.

Disclosures

All authors: No reported disclosures.
1697. Comparison of Candidemia in Patients in Neonatal Intensive Care Unit and Pediatric Patients and Big Data Analysis on Candidiasis and Candidemia in Korean Children
Authors: Choi Joon-sik , Yoon Yoonsun , Jun Kwak Soon , Kim Yae-Jean
Published: October 2019

Background

Fungal infection is a serious health threat in high-risk pediatric population. Data on pediatric epidemiology of candidemia in Korea are limited.

Methods

A retrospective chart review was performed in patients aged 0–18 years who were diagnosed with candidemia from 2009 to 2018 in a tertiary teaching hospital. Patients were divided into two groups; the neonatal group was comprised of babies with postnatal age 28 days or younger and any patients hospitalized in neonatal intensive care unit and rest of the patients were grouped into pediatric group. Only the first candidemia episode for each patient was included. In addition, the number of patients with candidemia and candidiasis and health cost was estimated among patients 19 years or younger who requested reimbursement to Health Insurance Review and Assessment Service (HIRA) Korea during the 9 year period from 2010 to 2018.

Results

Total 81 patients with candidemia were identified; 42 in the neonatal group and 39 in pediatric group. In neonatal group, prematurity was 95.2%, while hematology-oncology diseases were the most common underlying conditions in pediatric group. Among cultivated candida spp., C. parapsilosis was the most common pathogen (34.6%) followed by C. albicans (32.1%) and C. glabrata and C. tropicalis (11.1%, respectively). In neonatal group, C. parapsilosis (n = 17, 40.5%), C. albicans (n = 16, 38.1%), C. glabrata (n = 5, 11.9%) and unidentified species non-albicans candida (n = 4) were isolated. In pediatric group, C. parapsilosis (n = 11, 28.2%), C. albicans (n = 10, 25.6%), C. tropicalis (n = 9, 23.1%), C. glabrata (n = 4, 10.3%), C. krusei (n = 2), C. orthopsilosis (n = 1), C. lusitaniae (n = 1), C. kefyr (n = 1) were isolated. From HIRA data analysis, 47 patients were found to have candidemia and health cost was estimated as 1.27 million dollars and 66,286 patients were found to have candidiasis and health cost was 2.14 million dollars.

Conclusion

Discrepancies in numbers for candidemia between national reimbursement data and our retrospective data implies a significant underestimation of candidemia. Increased awareness for fungal infection documentation is needed to better estimate the true burden of invasive candida infection in the pediatric population.

Disclosures

All authors: No reported disclosures.
1703. Bacterial or Fungal Co-Infection in Patients with Mucormycosis
Authors: Choi Sungim , Son Hyo-Ju , Jung Jiwon , Jae Kim Min , Pil Chong Yong , Lee Sang-Oh , Choi Sang-Ho , Hee Woo Jun , Soo Kim Yang , Kim Sung-Han
Published: October 2019

Background

There is a growing concern on infections with multiple organisms including fungi in patients with mucormycosis. However, limited data are available on co-infection in patients with mucormycosis.

Methods

Patients with proven mucormycosis were retrospectively enrolled at a tertiary hospital from July 2009 to January 2019. Proven mucormycosis was defined as positive fungal culture result for mucormycosis from a sterile biopsy specimen and/or histologic evidence of tissue invasion of hyphae with positive mucormycosis immunohistochemistry test result. We reviewed other pathogens isolated from sterile or non-sterile sites before and after 7 days from the biopsy for infected tissue that suggested invasive fungal infection.

Results

A total of 61 patients with proven mucormycosis were analyzed. The primary site of infection was as follows; lung (n = 38, 62.3%), rhino-sinus (n = 21, 34.4%), and orbito-cerebral (n = 15, 24.6%). Based on sterile culture results, 4 patients (6.6%) had the evidence of co-infection with other fungi including Candida species (from 3 cases; C. albicans from 1, C. glabrata from 1 and C. krusei from 1), A. flavus (1), and F. solani (1), and 23 patients (37.7%) had the evidence of co-infection with bacteria including E. faecium (VRE) (8), P. aeruginosa (5),coagulase-negative staphylococci (5), methicillin-susceptible S. aureus (4) and others. Based on non-sterile culture results, 10 patients (16.4%) had the evidence of co-infection with fungi other than mucormycosis including Aspergillus species (5, A. fumigatus from 1, Aspergillus not fumigatus from 1 and A. oryzae from 1), Candida species (5, C. albicans from 2, C. tropicalis from 2 and C. glabrata from 1), Penicillium species (1), S. cerevisiae (1) and P. jirovecii (1), and 24 patients (39.3%) had evidence of bacterial co-infection including S. maltophilia (5), methicillin-resistant S. aureus (5), E. faecium (VSE) (3), K. pneumonia (3), P. aeruginosa (3), and others.

Conclusion

Bacterial or fungal co-infections appear to frequently occur as appreciated before in patients with mucormycosis. These data provide us important information to select empirical antifungal and antibacterial agents.

Disclosures

All authors: No reported disclosures.
1725. Shear Forces Induce a Transient, Calcineurin-Dependent Hyper-Virulent Phenotype in Mucorales via Soluble Factors
Authors: Wurster Sebastian , Tatara Alexander M , Albert Nathaniel D , Mikos Antonios G , Ibrahim Ashraf S , Bruno Vincent M , Kontoyiannis Dimitrios P
Published: October 2019

Background

Myocutaneous mucormycosis is encountered in settings of extreme mechanical forces such as combat-related blast injuries or natural catastrophes. It is unclear whether the virulence of Mucorales is affected by mechano-biological factors such as shear forces (SF).

Methods

Spores of clinical strains of Rhizopus arrhizus, Rhizomucor pusillus, and Mucor circinelloides (107/mL in PBS) were either kept in static culture (control) or exposed to shear forces (SF) by magnetic stirring for 30 minutes. Mycelial expansion was monitored in the IncuCyte time-lapse microscopy system. For in vivo studies, the dorsal thorax of wild-type Drosophila melanogaster flies (n = 66–76 per condition) was pricked with a needle dipped in control or SF-exposed spore solutions. Flies were also infected with non-exposed spores suspended in cell-free supernatant taken from SF-exposed spores. Survival was monitored for 7 days post-infection.

Results

Growth rates and morphogenesis of all isolates were not altered by SF. However, SF-exposed spores of all tested Mucorales isolates exhibited increased pathogenicity in the fly model (7-day survival: SF 8–14%, control 36–44%, P < 0.001). Introducing different resting periods after SF resulted in gradual attenuation of the hyper-virulent phenotype, with survival rates of infected flies returning to the level seen with non-SF-exposed spores after 120 min post-SF resting (Panel A). To gain a mechanistic insight, we added cyclosporine A (CsA, 100 µg/mL) during shear challenge. Compared with SF-exposed spores, CsA addition improved 7-day survival of R. arrhizus-infected flies from 1% to 29% (P < 0.001), whereas the pathogenicity of non-SF-exposed spores was not influenced by CsA. Interestingly, supernatants from SF-exposed R. arrhizus rendered non-exposed spores hyper-virulent (Panel B, P = 0.003).

Conclusion

SF induces a transient hypervirulent phenotype of Mucorales. Our findings suggest that soluble mediators contribute to increased pathogenicity. Largely attenuated hyper-virulence in the presence of CsA corroborated the previously described relevance of the calcineurin pathway in fungal mechano-biology. RNA sequencing studies are in progress to identify epigenetic alterations in Mucorales following SF.

Disclosures

All authors: No reported disclosures.
1726. Candida albicans Virulence Genes Induced During Intra-abdominal Candidiasis (IAC) in the Absence of Antifungal Exposure Mediate Echinocandin Resistance
Authors: Clancy Cornelius J , Samanta Palash , Cheng Shaoji , Squires Kevin , Nguyen Minh-Hong
Published: October 2019

Background

We developed and validated a mouse model of C. albicans IAC that mimics peritonitis and abscesses (IAA) in humans, and that is amenable to temporal–spatial transcriptional profiling and virulence studies.

Methods

We measured C. albicans SC5314 gene expression by RNA-Seq (RiboPure extraction; Illumina MiSeq) in triplicate during early peritonitis (within 30 minutes of infection), late peritonitis (24 hours) and IAA (48 hours). Differential expression was defined by ≥2-fold differences at false discovery rate ≤0.01.

Results

≥7 million C. albicans reads were detected in each experiment. 67% of C. albicans reads mapped to coding sequences, covering 93% of open reading frames. The 50 C. albicans genes most highly expressed during early peritonitis were associated with pH (including RIM101 and PHR1) and oxidative stress responses, and adhesion/hyphal growth (e.g., ALS3, HWP1, ECM331, SAP6). The corresponding 50 C. albicans late peritonitis genes were associated with neutrophil/macrophage responses and nutrient acquisition (glyoxylate cycle, fatty acid β-oxidation, iron homeostasis). Responses within IAA included DNA damage and iron metabolism, reflecting stress response and nutrient/metal limitation. The top 50 core gene responses for all stages were associated with adhesion, stress response, and glucose transport. Among the most up-regulated genes in late peritonitis and IAA compared with early peritonitis were those involved antifungal drug resistance (CDR family, MDR1, FLU1, and ERG family), although mice were not exposed to antifungals. Null and reconstitution mutants for genes involved in adhesion (ALS3), copper transport (CCC2), DNA (DDI1) and cell wall damage responses (DAP1 homologs), and glycerol biosynthesis (RHR2) were attenuated for virulence in temporal-spatial fashion during peritonitis and IAA, and/or hyper-susceptible to phagocytosis and echinocandins (table).

Conclusion

C. albicans relies upon diverse biologic processes to cause peritonitis and IAA. Multiple genes induced in response to stress during IAC mediate virulence, phagocyte, and echinocandin resistance. Therefore, pathogenic strategies used by C. albicans during IAC may lessen responses to echinocandin treatment, even in the absence of drug exposure or FKS mutations.

Disclosures

All authors: No reported disclosures.
1727. Candida albicans Phosphatidylinositol-(4,5)-Bisphosphate (PIP2) Directs Aberrant Cytokinesis and Septation in Response to Echinocandins, Which Correlates with Fungicidal Activity and Attenuated Virulence
Authors: Badrane Hassan , Nguyen Minh-Hong , Clancy Cornelius J
Published: October 2019

Background

We previously showed that highly dynamic PIP2, septin, and PKC-Mkc1 cell wall integrity pathway responses correlate with echinocandin activity against C. albicans and attenuated virulence during invasive candidiasis. Our objectives were to determine whether PIP2 dysregulation in response to an echinocandin results in aberrant localization of the septation and cytokinesis apparatus, and to quantitate aberrant localization.

Methods

Live cell imaging (LCI) was performed for 3 hours (Nikon A1 confocal microscope, NIS Elements software; Tokyo) on C. albicans irs4 mutant and wild-type SC5314 expressing fluorescently labeled PIP2 and Cdc10 (septin), Act1 (actin), or Myo1 (myosin).

Results

C. albicans irs4, in which PIP2 5’-phosphatase is disrupted, mislocalizes PIP2 and septins, and over-activates the PKC-Mkc1 pathway in a manner similar to echinocandin-exposed C. albicans SC5314. LCI revealed that PIP2 co-localized with Act1 and Myo1 at aberrant sites in C. albicans irs4, similar to PIP2-Cdc10 co-localization. 83% of co-localizing patches were in cells undergoing active cytokinesis. 78% of patches were at sites of cytokinesis, which reflected both normal budding and abnormal, wide-necked budding; 5% of patches localized to aberrant plasma membrane sites during cytokinesis. 17% of co-localizing patches were in cells that were not undergoing active cytokinesis. 6% of patches were at old cytokinesis sites; 11% of patches were at aberrant plasma membrane sites. Similar PIP2-septin-actin-myosin dysregulation was observed in C. albicans SC5314 immediately upon 4x MIC caspofungin exposure (Figure; videos).

Conclusion

Dysregulated C. albicans PIP2 recruits the septation and cytokinesis apparatus, including septins, actin, and myosin, to sites of incomplete cytokinesis at bud necks and to sites of aberrant, ectopic septation in plasma membranes of both dividing and non-dividing cells. Our data support a model in which a dysregulated PIP2 response is triggered immediately upon echinocandin exposure, over-activates the PKC-Mkc-1 pathway, and correlates with the extent of fungicidal activity and attenuated virulence. PIP2-septation-cytokinesis dysregulation is likely to lead to C. albicans death by promoting cell lysis, or selecting cells to undergo apoptosis.

Disclosures

All authors: No reported disclosures.
1749. A Nationwide Survey of Cytomegalovirus Prevention Strategies in Kidney Transplant Recipients in a Resource-Limited Setting
Authors: Bruminhent Jackrapong , Bushyakanist Asalaysa , Kantachuvesiri Susarak , Kiertiburanakul Sasisopin
Published: October 2019

Background

Cytomegalovirus (CMV) causes morbidity in kidney transplant (KT) recipients. Strategies to prevent this infection in resource-limited settings have been unreliably implemented and under-explored. We investigated CMV prevention strategies utilized among transplant centers in Thailand.

Methods

A questionnaire on CMV prevention strategies for KT recipients was developed using a web-based electronic survey website (www.surveymonkey.com). The survey was delivered to 31 transplant centers in Thailand. One infectious disease physician (ID) and one nephrologist (NP) from each center were included.

Results

There were 43 respondents from 26 (84%) transplant centers including 26 (60%) IDs and 17 (40%) NPs. The majority worked in a public hospital setting (63%) and had encountered KT recipients for at least 2 years (74%). Forty-one (98%) physicians agreed on the necessity of CMV prevention. Of these, 34 (81%) physicians implemented prevention strategies for their patients. Interventions included preemptive approaches (47%), prophylaxis (44%), hybrid approaches (3%); surveillance after prophylaxis (3%), and CMV-specific immunity-guided approaches (3%). For CMV-seropositive KT recipients, use of preemption (84%) exceeded prophylaxis (12%). However, 81% of the former preferred targeted prophylaxis in patients receiving anti-thymocyte globulin therapy. Sixty-five and 93% of physicians started preemptive therapy when plasma CMV DNA loads reached 2,000 and 3,000 copies/mL (1,820 and 2,730 IU/mL), respectively. A significantly greater percentage of NPs initiated preemptive therapy at a plasma CMV level of 1,820 IU/mL compared with IDs (88% vs. 50%, [P = 0.02]). The most common barrier to prevention strategy implementation was financial inaccessibility of oral valganciclovir (67%) and quantitative CMV DNA testing (12%). The majority (81%) felt that a guideline would allow physicians to implement CMV prevention strategies for their patients.

Conclusion

Most physicians agreed on a need for preemptive approaches, although prophylaxis was targeted in those receiving intense immunosuppression. Guidelines and financial accessibility could improve CMV prevention strategy implementation in Thai KT recipients.

Disclosures

All authors: No reported disclosures.