Grant Investigator Research Articles

2046. FungiScope™: News on the Global Emerging Fungal Infection Registry

BackgroundNumbers of rare invasive fungal diseases (IFD) are rising worldwide due to increasing patient population at risk. To broaden the knowledge on epidemiology of rare IFD and eventually improving diagnosis and clinical outcome, FungiScope™, a global registry for rare IFD, has been initiated.MethodsFungiScope™ uses web-based data capture (www.clinicalsurveys.net). Eligible are cases with proven or probable infection due to rare, non-endemic fungi. Data collected include demographics, underlying conditions, clinical presentation, diagnostics, antifungal therapy and outcome. Clinical isolates are collected for centralized identification, susceptibility testing and exchange between collaborators.ResultsTo date, 728 valid cases of rare IFD from 41 countries are included in the registry: IFD due to Mucormycetes (n = 358), Fusarium spp. (n = 87), rare yeasts (n = 83), dematiaceae (n = 69), and Scedosporium spp. (n = 55) are the most frequently reported. FungiScope™ is supported by central labs in the Czech Republic, India, Russia, and Spain. Recently, FungiScope™ collaborators jointly published results on (I) invasive mucormycosis in children analyzed together with cases from the registry study Zygomyco.net, (II) disseminated fusariosis in 10 children, and (III) invasive infections due to Saprochaete and Geotrichum spp. in 23 patients.ConclusionThe clinical relevance and by this the awareness of emerging IFD is increasing. FungiScope™ is a valuable resource used for collaborative studies on rare IFD. Operating and management of the registry requires considerable effort to ensure high data quality for comprehensive analyses, which provide insights into current clinical management of the diseases and thus, hold the potential to identify strategies for early diagnosis and effective treatment.Disclosures M. J. G. T. Vehreschild, Pfizer: Speaker’s Bureau, Speaker honorarium; MSD/Merck: Consultant and Speaker’s Bureau, Consulting fee and Speaker honorarium; Gilead Sciences: Research Contractor and Speaker’s Bureau, Research grant and Speaker honorarium; Organobalance: Speaker’s Bureau, Speaker honorarium; Astellas Pharma: Consultant, Research Contractor and Speaker’s Bureau, Consulting fee, Research grant and Speaker honorarium; 3M: Research Contractor, Research grant; DaVolterra: Research Contractor, Research grant; Berlin Chemie: Consultant, Consulting fee. J. Vehreschild, Merck / MSD: Consultant, Research Contractor and Speaker’s Bureau, Consulting fee, Research grant and Speaker honorarium; Gilead: Consultant, Research Contractor and Speaker’s Bureau, Consulting fee, Research grant and Speaker honorarium; Pfizer: Research Contractor and Speaker’s Bureau, Research grant and Speaker honorarium; Astellas Pharma: Consultant, Research Contractor and Speaker’s Bureau, Consulting fee, Research grant and Speaker honorarium; Basilea: Consultant, Research Contractor and Speaker’s Bureau, Consulting fee, Research grant and Speaker honorarium; Deutsches Zentrum für Infektionsforschung: Member, Research Contractor and Speaker’s Bureau, Research grant and Speaker honorarium; Uniklinik Freiburg/Kongress und Kommunikation: Speaker’s Bureau, Speaker honorarium; Akademie für Infektionsmedizin: Speaker’s Bureau, Speaker honorarium; Universität Manchester: Speaker’s Bureau, Speaker honorarium; Deutsche Gesellschaft für Infektiologie: Member and Speaker’s Bureau, Speaker honorarium; Ärztekammer Nordrhein: Speaker’s Bureau, Speaker honorarium; Uniklinik Aachen: Speaker’s Bureau, Speaker honorarium; Back Bay Strategies: Speaker’s Bureau, Speaker honorarium; Deutsche Gesellschaft für Innere Medizin: Member and Speaker’s Bureau, Speaker honorarium. O. A. Cornely, Amplyx Pharmaceuticals, Basilea Pharmaceutica, F2G, Gilead Sciences, MSD Sharp and Dohme, Scynexis Inc.: Consultant, Consulting fee; Amplyx Pharmaceuticals, Basilea Pharmaceutica, F2G, Gilead Sciences, MSD Sharp and Dohme, Scynexis Inc.: Grant Investigator, Research grant; Basilea Pharmaceutica, Gilead Sciences, MSD Sharp and Dohme, Pfizer: Speaker’s Bureau, Speaker honorarium.

930. HCV Treatment Is Associated With a Reduced Risk of Cardiovascular Disease Events: Results From ERCHIVES

BackgroundStudies reporting on the association between HCV and cardiovascular disease (CVD), and effect of HCV treatment upon future risk of CVD have shown mixed results.MethodsWithin ERCHIVES (Electronically Retrieved Cohort of HCV Infected Veterans), we identified all persons treated for ≥7 weeks and propensity-score-matched group who never received HCV treatment. We excluded those with HIV, HBV, or previously diagnosed CVD. Incidence rate (per 1,000 person-years) and risk factors for CVD events (Cox proportional hazards analysis) were determined for various treatment groups. CVD events were identified using ICD-9CM/ICD-10 codes. Kaplan–Meier plots were generated to show and compare CVD-free survival by treatment status and attainment of SVR.ResultsAmong 32,575 treated and same number of untreated persons in the final dataset, median age was 58 years, 27% were Black race, and 96% were male. The incidence rate for CVD events/1,000 person-years (95% CI) among the treated was 19.10 (17.79, 20.50) vs. 32.37 (30.51, 34.33) among the untreated (P < 0.01). Treatment with a DAA regimen (vs. PEG/RBV; HR [95% CI] 0.68 [0.53,0.88]) and achieving SVR (HR [95% CI] 0.76 [0.63,0.92]) were associated with a lower risk of incidence CVD event (table). Kaplan–Meier curves demonstrated that untreated persons had a shorter CVD event-free survival during 30 months of follow-up compared with the treated persons. (figure; log-rank P < 0.0001)ConclusionHCV treatment is associated with a reduction in incident CVD events. Directly acting antiviral regimens (vs. PEG/RBV) and attainment of SVR (vs. no SVR) are associated with a lower risk of incident CVD events. Disclosures A. Ajwad Butt, Gilead: Grant Investigator, Research grant.

1410. Novel Framework to Compare the Effectiveness of Tazobactam, Relebactam and Avibactam Against Extended-Spectrum β-Lactamase-Producing Enterobacteriaceae

BackgroundResistance mediated by extended-spectrum β-lactamases (ESBLs) presents a serious challenge in the treatment of Gram-negative pathogens. ESBLs confer resistance to most β-lactams which may be reversed with the addition of an active β-lactamase inhibitor (such as tazobactam, relebactam and avibactam). However, various ESBLs may display different susceptibilities to these inhibitors, which could impact efficacy. We propose a framework for comparing the efficacy of these inhibitors when combined with the same β-lactam.MethodsThree clinical isolates of K. pneumoniae harboring CTX-M-15 and one E. coli with SHV-12 were used. The susceptibility of each isolate to piperacillin was determined by broth dilution using escalating concentrations of tazobactam, relebactam and avibactam. Similar experiments were subsequently conducted with ceftazidime. The resulting minimum inhibitory concentrations (MICs) were mapped as response to inhibitor concentration using an inhibitory Emax model. The best-fit model parameters were compared for each isolate-inhibitor combination.ResultsIn all scenarios, MIC reductions were observed in the presence of increasing inhibitor concentrations. The MIC reduction for each isolate was well fitted to inhibitor concentrations (r2 ≥ 95%). IC50 estimates reflected the sensitivity of the isolates to each inhibitor, while Imax captured the maximum extent of MIC reduction. With piperacillin, IC50 values ranged from 1.36 to 35.25µg/mL for tazobactam, 2.32–15.82 µg/mL for relebactam and 0.62–2.37 µg/mL for avibactam. Imax values were 4.75–6.99, 6.56–9.77 and 7.83–11.22 for tazobactam, relebactam and avibactam, respectively. Similar trends in IC50 and Imax were observed with ceftazidime as the β-lactam.ConclusionWe illustrated a simple structural model capable of comparing the performance of different inhibitors. This platform may be used to identify the optimal pairing of various β-lactams and β-lactamase inhibitors for individual isolates.Disclosures V. Tam, European Union’s Seventh Framework Programme: Grant Investigator, Research grant.

637. Β-Lactam (BL) Antibiotics Promote an IL-1β Response in Patients with Staphylococcus aureus Bacteremia (SaB)

BackgroundBL therapy has been associated with reduced SaB duration compared with non-BL therapy. It has been shown that patients with SaB who fail to generate increased serum IL-1β are at risk for prolonged SaB (> 4 days duration), a predictor of mortality. This suggests a major role for the IL-1β host response in prompt clearance of SaB. Furthermore, BL result in reduced peptidoglycan cross-linking, reduced peptidoglycan O-acetylation, and increased alpha-toxin expression, all of which have independently been shown to enhance IL-1β release. This study aims to show that BL therapy results in a more robust IL-1β host response compared with non-BL therapy to explain, in part, more rapid SaB clearance.MethodsFifty-nine patients (47 MRSA and 12 MSSA) with diverse SaB sources, including endovascular, extravascular (e.g., pneumonia), and catheter-related infections were included. In the first 48 hours, patients were treated with either BL, including oxacillin, ceftaroline, or cefazolin (n = 24), vs. non-BL vancomycin or daptomycin (n = 35). IL-1β concentrations were determined by ELISA on serum samples obtained on Days 1, 3 and Day 7 after bacteremia onset and compared between groups by Mann–Whitney U test.ResultsPatients in BL and non-BL groups had similar IL-1β concentrations on Day 1 of bacteremia (median BL 6.1 pg/mL vs. non-BL 2.8 pg/mL, P = 0.090). BL-treated patients had significantly higher IL-1β serum concentrations on Day 3 (median 7.54 mg/mL vs. 1.9 pg/mL; P = 0.007) and Day 7 (12.52 pg/mL vs. 1.56 pg/mL, P = 0.016) when compared with non-BL-treated patients. BL therapy resulted in 23% and 105% increase in IL-1β at Days 3 and 7, respectively, while non-BL treatment resulted in 32% and 44% reduction in IL-1β. The median duration of SaB was similar between BL and non-BL-treated patients (2.5 vs. 2.0 days, respectively, P = 0.590).ConclusionGiven that a lack of inflammasome-mediated IL-1β production is associated with prolonged SaB, the significant increases in IL-1β levels in patients treated with BL has important therapeutic implications. Previously observed reduced duration of MRSA bacteremia with the addition of BL to vancomycin may have its basis on enhancing IL-1β release. A therapeutic regimen of vancomycin or daptomycin in combination with BL to treat MRSA bacteremia and use of BL therapy in MSSA bacteremia is strongly advised to improve outcomes based on these results.Disclosures G. Sakoulas, Allergan: Consultant and Speaker, Consulting fee and Speaker honorarium. Sunovion: Speaker, Speaker honorarium. The Medicines Company: Speaker, Consulting fee. Paratek Pharmaceuticals: Consultant, Consulting fee. Cidara Therapeutics: Scientific Advisor, None. Arsanis Pharmaceuticals: Scientific Advisor, None. W. Rose, Merck: Grant Investigator, Research grant.

1050. Oral Antibiotics for the Treatment of Gram-Negative Bloodstream Infections: Prescribing Practices and Outcomes at a Large Academic Medical Center

BackgroundThere is limited data to guide the use of oral (PO) antibiotics for the treatment of Gram-negative (GN) bloodstream infection (BSI). The objective of this study was to describe the characteristics and outcomes at a large academic medical center.MethodsRetrospective observational cohort of adult patients (age ≥18 years) with at least one blood culture positive for aerobic Gram-negative organism(s) treated with antibiotic therapy (IV or oral [PO]) at University of Medical Center from November 2015 to May 2017. Oral antibiotics were described based on bioavailability. The primary outcome of interest was 30-day infection-related readmission. Secondary objectives included evaluation of patient characteristics associated with PO antibiotic use.ResultsDuring the defined study period 310 patients met inclusion; 113 (36.5%) were switched to PO antibiotic therapy for the treatment of GN BSI within a median of 5 (IQR 3–11) days. Oral antibiotics were initiated at discharge for 50 (44%) of patients switched. Patients switched to PO were less likely to have has a stay in the ICU (24.8% vs. 47.7%, P < 0.0001) and were less likely to have an ID consult (57.5% vs. 71.1%, P = 0.034). There was no difference in median Charlson Comorbidity Score (2, IQR 0–4). The most common sources of infection among those switched to PO agents were urinary (50, 44.2%) and intra-abdominal (25, 22.1%). The majority of patients were placed on a PO agent with high bioavailability (61, 54%), which included levofloxacin and moxifloxacin. There was a slightly higher proportion of use of high (vs. low) bioavailable antibiotics in patients with ID consult compared with those without (59% vs. 41%, P = 0.053). PO antibiotics were more frequently prescribed for patients discharged home (78, 69%) compared with patients discharged to Rehab/Short-term facility (28, 24.8%). Thirty-day hospital readmission was more common among the patients treated with PO antibiotics (18.6 vs. 8.1%, P = 0.006); however, ID-related readmission was rare (0.9% vs. 1%, P = 0.91).ConclusionUrinary and intra-abdominal sources and home discharge were common among those with PO antibiotic use. ID-related outcomes were similar among those treated with IV vs. PO agents. More research is necessary to determine optimal time to PO antibiotic switch.Disclosures K. Claeys, Nabriva: Scientific Advisor, Consulting fee. Melinta: Scientific Advisor, Consulting fee. E. Heil, ALK-Abelló: Grant Investigator, Research grant.

613. Transmission of Influenza Virus in Mother and Infant Transmission Events in Nepal

BackgroundInfluenza immunization of pregnant women provides protection of the infant against influenza disease. A potential mechanism of protection is prevention of maternal illness that may result in secondary transmission to infants. We aim to characterize influenza transmission in mother–infant pairs.MethodsPregnant mothers were enrolled in a randomized controlled trial of influenza immunization in rural Nepal from April 2011 to April 2013. Mothers and infants were surveyed weekly until 180 days post-partum for respiratory illness and mid-nasal swabs were collected at time of illness and tested for influenza virus by reverse-transcriptase polymerase chain reaction (RT-PCR). We defined a transmission episode as a mother–infant pair with an influenza-positive illness within 14 days of each other. Influenza viruses were strain-typed by RT-PCR and/or mass spectrometry.ResultsSeventeen mother–infant transmission episodes occurred with maternal illness preceding infant illness in 12 (70.6%). Of transmission pairs, 12 (70.6%) were influenza B, three (17.6%) H3N2 influenza A, one (5.9%) H1N1 influenza A, and one (5.9%) unspecified influenza A. Five (29.4%) mothers received the influenza vaccine. Successful strain-typing with RT-PCR/mass spectrometry of 11 pairs revealed that 10 (90.9%) were synonymous strains. Figure 1 shows the start of respiratory symptoms and virus type associated with influenza illness in the 17 mother–infant pairs.ConclusionMothers are an important source of infant influenza infection. Transmission was confirmed with nearly all paired transmissions demonstrating a similar strain. The majority of transmission events occurred in nonvaccinated mother–infant pairs. Figure 1: Influenza transmission events in mother–infant pairs. Symbols represent first day of respiratory symptoms associated with influenza-positive illness.Disclosures J. Englund, GlaxoSmithKline: Investigator, Research grant. MedImmune: Investigator, Research grant. Gilead: Investigator, Research grant. Novavax: Investigator, Research grant. Chimerix: Investigator, Research grant. Alios: Investigator, Research grant. H. Chu, Sanofi-Pasteur: Grant Investigator, Grant recipient.

226. An Emergency Department Antimicrobial Stewardship Intervention to Improve Antibiotic Selection and Duration for Skin and Soft-tissue infections in Adult and Pediatric Outpatients

BackgroundSkin and soft-tissue infections (SSTIs) are common infections seen in the Emergency Department (ED). However, adherence to IDSA guidelines for treatment, in terms of antibiotic selection and duration, is poor. Objective. To evaluate the ability of a multifaceted intervention to improve adherence to the 2014 IDSA guidelines for the management of SSTIs in an academic adult and pediatric ED.MethodsA non-randomized study of a multifaceted intervention for SSTI in the ED was employed which included educational presentations, implementation of an electronic order set based on 2014 IDSA guidelines, dissemination of ED-specific antibiograms, monthly departmental peer comparisons, and bimonthly individual feedback. SSTI visits were identified using ICD-10 codes L00, L02.x1, L03, L08.89, and L08.9. The primary endpoint was adherence to IDSA guidelines. Outcomes during the preintervention and intervention periods, adjusting for patient demographics and infection characteristics, were compared with the same time periods at a control site (CS) that did not implement the intervention.ResultsThere were 583 SSTIs included in the study [intervention site (IS) =283, CS =300] split over three time periods: preintervention (October 2015–March 2016; IS = 130, CS = 150), intervention (October 2016–March 2017; IS = 99, CS = 150), and postintervention (April 2017–July 2017; IS = 54, CS = 0). At the IS, adherence was 41% prior to the intervention and 51% during the intervention. At the CS adherence was 19% and 25% during the two time periods. In the adjusted model, adherence at the IS was higher during the intervention compared with the preintervention period [adjusted odds ratio (aOR) 2.26 (95% CI 1.24–4.10)]. Adherence in the postintervention period was similar to the preintervention period [aOR 0.94 (0.45–1.97)]. No changes were seen during the two time periods at the CS [aOR 1.00 (0.53–1.89)].ConclusionImplementation of an antimicrobial stewardship intervention for SSTI significantly improved adherence to IDSA guidelines; however, adherence regressed after the intervention ended. Additionally, adherence was generally poor in all time periods and at both sites. Further research is needed to understand barriers and challenges to implementation of SSTI guidelines in ED settings.Disclosures L. G. Miller, Merck: Grant Investigator, Research grant

2461. Safety of Quadrivalent Meningococcal Polysaccharide Diphtheria Toxoid-Conjugate Vaccine in Adolescents

BackgroundThe first quadrivalent meningococcal conjugate vaccine (MenACWY-D) was recommended for use in adolescents in 2005. Soon after, case reports of Guillain-Barre syndrome (GBS) following vaccination prompted subsequent studies, with a meta-analysis concluding that the attributable risk of GBS after MenACWY-D is unlikely to exceed 1 case per million vaccinations. We conducted a retrospective cohort study in the Vaccine Safety Datalink to assess the risk of 10 outcomes, including GBS, following MenACWY-D.MethodsWe included adolescents (aged 11–18 years) vaccinated with MenACWY-D during the years 2005–2014. We identified pre-specified outcomes using ICD-9 (International Classification of Disease, version 9) codes. We used automated data only for Bell’s palsy, fever, seizure and syncope, and we confirmed incident cases by medical record review for acute disseminated encephalomyelitis (ADEM), acute transverse myelitis (ATM), anaphylaxis, chronic inflammatory demyelinating polyneuropathy (CIDP), GBS and Henoch-Schönlein purpura (HSP). We used a self-controlled risk interval design to estimate relative risk (RR).ResultsFollowing 1.4 million doses of MenACWY-D, we detected increased risks for fever in the 1–6 days following vaccination (RR 1.5, 95% confidence interval [CI] 1.3–1.7) and syncope on the day of vaccination (RR 5.8, 95% CI 4.1–8.3), but not for seizures (RR 1.1, 95% CI 0.7–1.9) or Bell’s palsy (RR 1.1, 95% CI 0.8–1.5). We detected no cases in the post-vaccination risk intervals for CIDP, ADEM or ATM. We detected few cases of the other outcomes resulting in relatively unstable RR estimates: anaphylaxis (RR 1.9, 95% CI 0.5–7.1), GBS (RR 2.5, 95% CI 0.6–10.0) and HSP (RR 1.6, 95% CI 0.7–3.3). We estimated that the attributable risk of GBS was 1.5 cases per million vaccinations (upper bound of one-sided 95% CI, 4.9).ConclusionIn a large retrospective cohort, we detected increased risks for syncope and fever, but not seizures or Bell’s palsy, following vaccination with MenACWY-D. Other outcomes were rare. Our findings, consistent with previous studies, suggest that the increased risk of GBS, if any, is likely small (<5 excess cases of GBS per million vaccinations).Disclosures N. P. Klein, Sanofi Pasteur: Investigator, Research grant. Merck: Investigator, Research grant. GSK: Investigator, Research grant. Pfizer: Investigator, Research support. Protein Science: Investigator, Research grant. MedImmune: Investigator, Research grant. Dynavax: Research Contractor, Grant recipient. M. L. Jackson, Novartis: Grant Investigator, Research support.

2073. Positive Clinical Impact of MALDI-TOF for the Management of Inpatient Pneumonia Without Additional Antimicrobial Stewardship (AS) Support

BackgroundMatrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry decreases time to identification (ID) and has been shown to improve antibiotic utilization when combined with real-time AS intervention. We assessed the impact of MALDI-TOF without additional AS support in patients with inpatient pneumonia.MethodsThis was a single-center quasi-experimental study of adult patients with a pneumonia who had a positive respiratory culture with bacteria that were identified by MALDI-TOF from August 2016–February 2017 (Pre-MALDI-TOF) and August–February 2018 (Post-MALDI-TOF). The primary endpoint was the time to initiation of optimal therapy before and after MALDI-TOF. The secondary endpoints included: clinical cure at 7 days; inpatient antibiotic duration; infection-related length of stay (LOS); overall LOS; excess antibiotic days; and costs. T-tests, Mann–Whitney U, and chi-squared tests were used for comparisons where appropriate.ResultsTable 1:Time to Optimal Therapy and Intervention OpportunitiesPre-MALDI-TOF (180)Post-MALDI-TOF (180) P-ValueTotal opportunities for interventions, n (%)152 (84)168 (93)0.007De-escalation performed, n/N (%)105/152 (69)124/152 (74)0.40Escalation performed, n/N (%)29/152 (19)34/152 (20)0.79Time to Identification, h, median, IQR63 [46–72]32 [24–46]<0.001Time-to-optimal therapy, hour, median, IQR73 [55–89]56 [48–73]<0.001Excess doses0 [0–1]1 [0–3]0.003Excess cost2,122.573,335.720.007Table 2:OutcomesPre-MALDI-TOFPost-MALDI-TOF P-ValueIn-hospital mortality7 (4)8 (4)0.79Inpatient duration of antibiotics, days, median, IQR7 [5–10]7 [5–9]1Infection related LOS, days, median, IQR7 [5–11]7 [5–9]0.09Overall hospital LOS, days, median, IQR14.5 [7–32]13 [6–29]0.26Clinical cure145 (81)150 (83)0.49ConclusionThe implementation of MALDI-TOF without AS support for pneumonia patients reduced the time to ID and optimal therapy but there were no significant differences in clinical outcomes. It did not positively impact excess antibiotic doses or costs.Disclosures J. Gallagher, Achaogen: Consultant, Consulting fee; Merck: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee and Research grant; Allergan: Consultant and Speaker’s Bureau, Consulting fee; Astellas: Consultant and Speaker’s Bureau, Consulting fee; Cempra: Consultant, Consulting fee; Cidara: Consultant, Consulting fee; CutisPharma: Consultant, Consulting fee; Paratek: Consultant, Consulting fee; Shionogi: Consultant, Consulting fee; Tetraphase: Consultant, Consulting fee; Theravance: Consultant, Consulting fee; The Medicines Company: Consultant, Consulting fee; Melinta: Speaker’s Bureau, Consulting fee.

2175. In vitro Potency of Ceftolozane/Tazobactam and Other Antipseudomonal β-Lactams Against P. aeruginosa

BackgroundChallenges due to multidrug resistant Gram-negative bacterial pathogens such as P. aeruginosa (PSA) are increasing globally. Suboptimal antimicrobial therapy of infections caused by PSA is associated with increased morbidity and mortality. As a result, antimicrobial susceptibility (%S) studies are pivotal to identifying trends in antimicrobial resistance that inform decisions regarding choice of antimicrobial therapy. This study assessed the in vitro potency of 7 antipseudomonal agents including ceftolozane/tazobactam against PSA collected from numerous sites across the United States.MethodsMultiple U.S. hospitals provided nonduplicate respiratory and blood isolates of PSA for potency testing. MICs against PSA were determined using broth microdilution methods according to CLSI for seven antimicrobials with antipseudomonal activity: aztreonam, cefepime, ceftazidime, ceftolozane/tazobactam, imipenem, meropenem and piperacillin/tazobactam. Susceptibility (%S) was defined per CLSI or FDA breakpoint criteria.ResultsFourteen hospitals geographically spread across the United States provided total of 560 PSA isolates. Of the antibiotics assessed, %S to C/T was the highest at 95% with an MIC50 of 1 µg/mL and MIC90 of 2 µg/mL. In comparison, other %S (MIC50/MIC90) were as follows: ceftazidime 76% (4/64); cefepime 75% (4/32); piperacillin/tazobactam 73% (8/128), meropenem 72% (0.5/16); aztreonam 65% (8/32) and imipenem 65% (2/16).ConclusionFor this geographically diverse PSA population, ceftolozane/tazobactam demonstrated the highest overall susceptibility (95%). Other antipseudomonal agents inclusive of the carbapenems displayed susceptibilities of 65–76%. In the era of escalating PSA resistance to the β-lactams, the potency of ceftolozane/tazobactam may represent an important clinical option.Disclosures D. P. Nicolau, Merck: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Speaker honorarium.

733. Incidence and Evaluation of the Change in Functional Status Associated with Respiratory Syncytial Virus Infection in Hospitalized Older Adults

BackgroundRespiratory Syncytial Virus (RSV) causes severe respiratory illnesses in infants and older adults. Mortality disproportionately affects the elderly, can exacerbate chronic cardiopulmonary conditions and may result in loss of function. The purpose of this study was to determine the incidence of RSV infection in hospitalized adults and evaluate functional changes associated with RSV hospitalization in older adults ≥60 years.MethodsAdults ≥18 years of age admitted with an acute respiratory infection (ARI) or exacerbation of chronic cardiopulmonary disease (e.g. CHF, COPD, asthma) preceded by an ARI within 14 days were screened. Subjects were included if hospitalized for ≥24 hours with laboratory confirmed RSV and residing in two catchment areas (Rochester, NY and New York, NY). Illness history, comorbidities and demographic characteristics were collected at enrollment. Enrolled subjects ≥60 years underwent functional status evaluation retrospectively 2 weeks prior to hospitalization, at enrollment, discharge and 2 months using the Lawton–Brody Instrumental Activity of Daily Living (IADL) Scale (0–8), Barthel (ADL) Index (0–100), MRC Breathlessness score (1–5) and Mini-Cog instrument.ResultsFrom October 2017 to March 2018, 2,883 adults hospitalized with ARI were tested and 322 (11%) positive for RSV. Seventy-two adults ≥60 years underwent functional assessment. Mean age was 75 years, 53% were female and 58% demonstrated impaired cognition on admission. Five subjects died during hospitalization and one prior to 2-month follow-up. Interim analysis of 2-month functional assessment was available for 39 subjects. RSV illness resulted in acute functional loss in almost all patients. Although there were no statistically significant differences between mean pre-hospitalization and 2-month functional scores, IADL (6.7 vs. 6.0, P = 0.27), ADL (90.4 vs. 88.5, P = 0.67) and MRC (2.96 vs. 2.7, P = 0.57), 23% of subjects required a higher level of care at discharge. Additionally, RSV hospitalization resulted in decreased ADL scores in 36% of subjects and worsening respiratory function in 18% assessed at 2 months (figure). ConclusionOlder adults hospitalized with RSV infection demonstrate acute functional decline which may result in prolonged loss of function in some patients.Disclosures A. Branche, Merck: Investigator, Grant recipient and Research grant. E. Granieri, Merck: Investigator, Research grant. E. Walsh, Merck: Investigator, Research grant. L. Finelli, Merck: Employee, Salary. A. R. Falsey, sanofi pasteur: Consultant and Grant Investigator, Consulting fee and Research grant. Gilead: Consultant, Consulting fee. Merck Sharpe and Dome: Investigator, Grant recipient. Janssen Pharmacueticals: Investigator, Grant recipient. Pfizer: Consultant, Research grant. Novavax: Consultant, none. A. Barrett, Merck: Investigator, Research support. L. Saiman, Merck: Investigator, Research grant.

2367. Infection Incidence and Utilization of Antimicrobials in Physician Office Infusion Centers (POICs)

BackgroundPOICs offer a controlled setting for safe and effective outpatient treatment of moderate to severe infections with intravenous antimicrobial agents (IVAA) and agents used in treatment of Clostridium difficile infection (CDI). These therapies are provided via in-office or home administration. This study provides an overview of nationwide incidence of outpatient infections and utilization of IVAAs through POICs.MethodsA retrospective review of our centralized database was conducted of patient infections and therapy courses provided in POICs nationally that included complete data for 2017. All patients receiving IVAAs and drugs for CDI were included, along with dose, frequency, duration and method of administration. Descriptive measures were used to analyze data.ResultsA total of 12,930 infections were treated in 10,136 patients during 2017 among 77 POICs. Of those, 41% were treated directly from the community setting, avoiding hospitalization. Age distribution was <18 years <1%, 18–65 years 63% and >65 years 36%. Infections comprised 11 major diagnostic groups, with 47 subgroups. The most common diagnoses treated were bone and joint (37%), skin and skin structure (23%), genitourinary (14%) and bacteremia/septicemia (8%). 101 patients (1%) were treated for CDI. Geographical distribution occurred in the Midwest, Northeast, South, and West portion of the United States, where diagnoses were similar for all areas except the Northeast. This area had a significantly lower incidence of bone and joint infections (P < 0.0001) and a higher incidence of genitourinary infections (P < 0.0001). Overall utilization included 52 different agents, with 98.5% antimicrobials, 1% antifungals and 0.5% antivirals. Ceftriaxone was the most frequently used antimicrobial representing 16% of the total use, followed by vancomycin (14.5%), daptomycin (14.2%) and ertapenem (11%). The most prevalent infections and utilization of respective drug therapy is noted in the table. ConclusionThis study provides an annual overview of outpatient infection incidence with the utilization of IVAAs and therapy for CDI. A wide range of moderate to severe infections were treated, often avoiding hospitalization. Treatment regimens were broad, utilizing a wide variety of drugs and enabling extensive patient management in the POIC setting.Disclosures L. J. Van Anglen, Merck & Co.: Grant Investigator, Research grant.

2261. Phosphaturia in HIV-Exposed Uninfected Neonates Associated With Maternal Use of Tenofovir Disoproxil Fumarate in Late Pregnancy

BackgroundOur recent study showed significantly lower bone mineral content (BMC) in HIV-exposed uninfected (HEU) neonates born to HIV-infected (HIV+) mothers who took tenofovir disoproxil fumarate (TDF) in late pregnancy compared with no TDF use. In this cohort we sought to understand possible mechanisms for lower BMC by comparing markers of bone metabolism and renal function with TDF exposure in HEU neonates.MethodsAmong a subset of HEU children in the multicenter (United States and Puerto Rico) observational Surveillance Monitoring for ART Toxicities (SMARTT) Cohort study, we enrolled neonates (≥36 weeks gestational age) of HIV+ mothers who took TDF for ≥8 weeks in the third trimester (TDF+) or no TDF in pregnancy (TDF-). In addition to BMC measures, we collected a blood and urine sample on each child ≤30 days of birth to measure serum creatinine, phosphate, 25-OH vitamin D, parathyroid hormone and urine creatinine, phosphate and N-terminal telopeptide. Standard equations were used to estimate proximal tubular phosphate reabsorption and glomerular filtration rate (eGFR). Comparisons were made by TDF exposure using Wilcoxon and Fisher’s exact tests. We fit linear models to compare TDF+ and TDF− for each assay by age in days at sample collection (slope), stratified by age group at sample collection time (0–3 days, 4–30 days).ResultsOf 160 HEU neonates (Black 71%, Hispanic 31%), 82 were TDF+ and 78 TDF−. Sociodemographic and anthropometric characteristics did not differ by TDF exposure in each age group. Within 0–3 days of life, TDF+ had a greater decline in serum creatinine (P = 0.04) and a greater increase in eGFR compared with TDF− (P = 0.06), but no difference in slope by TDF exposure within 4–30 days of life, nor in serum phosphate in either age group. Proximal tubular phosphate reabsorption was similar for both groups within the first 3 days of life, with a significantly greater decline in phosphate reabsorption between 4 and 30 days of life in the TDF+ compared with the TDF− group (P = 0.006, Figure 1). Bone markers did not differ by TDF exposure for either age group.ConclusionUrinary phosphate loss was increased among HEU neonates of mothers who took TDF in late pregnancy. This suggests proximal tubular dysfunction and may explain, at least in part, the decrease in BMC previously described. Disclosures R. Van Dyke, Giliad Sciences: Grant Investigator, Research grant.

1294. Acceptability and Feasibility of a Pharmacist-led Pre-exposure Prophylaxis Program in the Midwestern United States

BackgroundDespite evidence that HIV pre-exposure prophylaxis (PrEP) substantially reduces the risk of infection in at-risk populations, significant barriers exist to its prescription and use. Utilizing pharmacists may help increase patient access to PrEP services. We designed and implemented a novel pharmacist-led PrEP program in Omaha, Nebraska.MethodsOur pharmacist-led PrEP program was developed in the fall of 2016. Six pharmacists from four sites (one community pharmacy, two community-based clinics and one HIV-specialized clinic) were selected for participation based on interest, senior management support, and availability of appropriate infrastructure. All pharmacists received training for the provision of PrEP. Through a collaborative practice agreement, pharmacists met with patients individually, obtained a medical history, performed a risk assessment and point-of-care laboratory testing (HIV screen, creatinine, and syphilis), and collected samples for gonorrhea and chlamydia. They also provided medication and adherence counseling, and prescribed emtricitabine-tenofovir DF when appropriate. Pharmacists completed a survey reporting their experience after each visit. Presented here are patient demographics, retention rates, and pharmacist-reported experience from the first 6 months of the program.ResultsSixty patients enrolled in the pharmacist-led PrEP program between January and June 2017 and completed 139 visits. 95% of participants were men, 83% were white, 80% were privately insured, and 90% had completed some college or higher. The mean age of participants was 34 years (range 20–61 years) and 88% identified as men who have sex with men. 73% were retained in care at 3 months and 58% were retained in care at 6 months. To date, no patient has seroconverted. Pharmacists reported feeling comfortable performing point-of-care testing at all visits and only reported feeling uncomfortable counseling patients on three occasions (2.2%). Finally, pharmacist-reported workflow disruption only occurred on 1 occasion (0.7%).ConclusionImplementation of a pharmacist-led PrEP program is feasible, associated with high rates of pharmacist acceptability, and results in retention rates that are comparable to other real-world PrEP programs.Disclosures S. Bares, Gilead: Grant Investigator, Grant recipient. S. Swindells, Merck: Investigator, Research support. ViiV: Investigator, Research support.

1821. Understanding the Components and Calculation of the SAAR, Illustrative Data

BackgroundThe standardized antimicrobial administration ratio (SAAR) compares each hospital’s observed to predicted days of antimicrobial therapy. However, confusion exists about how hospital-level, seasonal, and hospital-peer-based variations in antibiotic use might impact an institution’s SAAR. We characterized the impact of each of these three types of variation on predicted SAARs utilizing local NHSN data.MethodsAnalysis of antibiotic consumption data from an academic medical center in Chicago, IL was conducted. SAAR and antimicrobial days per 1,000 days present (AD/1,000DP) were compiled in monthly increments from 2014 to 2016.Antimicrobial consumption was aggregated and classified into agent categories according to NHSN criteria. Month-to-month changes in both the SAAR and AD/1,000DP were evaluated. Azithromycin AD/1,000DP from 2012 through 2017 were explored for seasonal variation as defined as >20% increase in AD/1,000DP from each quarter to the overall mean AD/1,000DP for all months. A simulation was performed to explore the potential effect of seasonality on the SAAR. Demographic covariates within the SAAR model were altered while holding constant observed antibiotic use; thus we were able to observe the potential impact of demographics. Finally, a simulation explored the effect of altered consumption at other hospitals on a local institution’s SAAR.ResultsAcross all antibiotic agent categories for both ICU (n = 4) and general wards (n = 4), the average matched-month percent change in AD/1,000DP was highly predicted and correlated with the corresponding change in SAAR (Figure 1, Pearson’s r = 0.99). The monthly mean ± SD AD/1,000DP was 235.0 (range 47.2–661.5), and the mean ± SD SAAR was 1.09 ± 0.26 (range 0.79–1.09) across the NHSN antibiotic agent categories. Five quarters were found to have seasonal variation in AD/1000DP for azithromycin (Figure 2). Simulations demonstrated that changing antimicrobial usage at comparator hospitals does not impact the local SAAR, and seasonal variation may cause fluctuating SAARs.ConclusionMonth-to-month changes in the SAAR mirror monthly changes in an institution’s AD/1,000DP. Seasonal variation can impact the SAAR, and the effect changing peer hospital antibiotic consumption is not currently captured by the SAAR methodology. Disclosures J. Liu, Merck: Grant fund from Merck, Research grant. D. Martin, Syneos Health: Employee, Salary. GlaxoSmithKline: Independent Contractor, Salary. M. H. Scheetz, Merck & Co., Inc.: Grant Investigator, Grant recipient. Bayer: Consultant, Consulting fee.

1295. Advancing the PrEP Continuum: A Novel Collaboration Between a Public Health Department and a Federally Qualified Healthcare Center in the Southern United States

BackgroundWhile pre-exposure prophylaxis (PrEP) is a promising strategy for HIV prevention, some high-risk persons have limited access to care, particularly Black and Latino men who have sex with men (MSM). Disparities also exist by region: the Southern United States accounts for over half of new HIV diagnoses but only a third of PrEP prescriptions. We evaluated a novel PrEP program based on a collaboration between a local department of public health (DPH) and a federally qualified health center (FQHC) providing care to underserved racial/ethnic minorities in Durham, North Carolina.MethodsIn May 2015, the Durham County DPH and Lincoln Community Health Center, an FQHC, developed a program to offer PrEP services using existing resources. The model included initial no-cost screening for sexually transmitted infections (STIs), hepatitis B/C, and HIV at the DPH STI clinic, followed by referral to the FQHC for PrEP services. We profiled the PrEP continuum for patients starting at program initiation until March 2018. For PrEP initiators and non-initiators, comparisons were made using Wilcoxon rank-sum test for continuous variables, and Chi-square or FisherÕs exact tests as indicated for categorical variables.ResultsOf 196 unique patients evaluated in the STI clinic and referred to the FQHC, 117 (60%) persons attended their initial PrEP appointments. Among these, 84 (43%) filled a PrEP prescription, 69 (35%) persisted in care for at least three months, and 58 (30%) reported >90% adherence at follow-up (see figure). Among those presenting for initial appointments (n = 117), more than half were Black (n = 62, 53%) and 21 (18%) were Latino. Most were MSM (n = 95, 81%) and 9 were transgender. Almost half (n = 55, 47%) were uninsured. We found statistically significant differences between PrEP initiators vs. noninitiators based on race/ethnicity (P = 0.02), insurance status (P = 0.05), and history of sex work (P = 0.05).ConclusionA collaborative model of PrEP care between a DPH and an FQHC in the Southern United States was able to reach predominantly Black and Latino MSM at high-risk for HIV. Although this program is sustainable, efforts to improve steps along the PrEP care continuum are still needed in this population. Disclosures A. Sena, Gilead: Grant Investigator, Research grant.

488. Oral Vancomycin Plus Intravenous Metronidazole for Severe Clostridium difficile Infection in Critically Ill Patients

BackgroundThere remains a paucity of data regarding optimal treatment of patients with severe Clostridium difficile infection (CDI) in the intensive care unit (ICU). Based on expert opinion, the 2018 SHEA-IDSA CDI Clinical Practice Guidelines recommend combination therapy (oral vancomycin [PO VAN] plus intravenous metronidazole [IV MDZ]) in fulminant CDI only. A 2015 study suggested a mortality benefit with combination therapy of PO VAN plus IV MDZ for ICU patients regardless of severity. The objective of this study was to determine the impact of combination therapy on clinical outcomes in ICU patients with severe CDI, compared with PO VAN monotherapy.MethodsSingle-center, retrospective, cohort of adult patients admitted to an ICU between April 2016 and April 2018 with a positive C. difficile nucleic acid amplification test and an order for PO VAN were screened for inclusion. Patients were excluded if they had life-threatening intra-abdominal complications, including toxic megacolon/emergent colectomy. The primary outcome was 30-day in-hospital all-cause mortality. In a subgroup analysis, patients were matched using Acute Physiology and Chronic Health Evaluation (APACHE) II scores. Logistic regression was conducted to identify clinical variables associated with mortality.ResultsOne hundred one patients were included; 47 received combination therapy with IV MDZ. Baseline characteristics were similar across groups, except patients in the IV MDZ group had a higher median white blood cell (WBC) count at diagnosis (18.4 vs. 13.9, P = 0.023) and were more likely to receive a higher dose (500 mg) of PO VAN (36.2% vs. 7.4%, P < 0.0001). Thirty-day mortality was 14.9% in the combination group vs. 7.4% in the monotherapy group, (P = 0.338). APACHE II Score was the only variable independently associated with 30-day mortality (OR = 1.13, 95% CI 1.03 – 1.24). There was no difference in probability of receiving IV MDZ based on APACHE II score. In a subgroup of patients matched by APACHE II score (n = 76), mortality remained nonsignificantly different (15.8% vs. 9.7%, P = 0.480).ConclusionOur data question the utility of IV MDZ in addition to PO VAN for ICU patients with severe CDI. There remains a possibility for confounding by indication in this retrospective analysis.Disclosures E. Heil, ALK-Abelló: Grant Investigator, Research grant. K. Claeys, Nabriva: Scientific Advisor, Consulting fee. Melinta: Scientific Advisor, Consulting fee.

1397. Comparative Efficacy of Human-Simulated Epithelial Lining Fluid (ELF) Exposures of Tedizolid (TZD) Against Methicillin-resistant Staphylococcus Aureus (MRSA) in Neutropenic (I−) vs. Immunocompetent (I+) Murine Models of Pneumonia

BackgroundTZD is an oxazolidinone with potent in vitro activity against Gram-positive pathogens, including MRSA. Limited data currently exist on the efficacy of TZD in the presence of neutropenia. Herein, we investigate the comparative efficacy of human-simulated ELF exposures of TZD against MRSA in I− and I+ murine models of pneumonia.MethodsFour MRSA isolates with TZD broth microdilution MICs of 0.5 mg/L were studied. BALB/c mice in I− groups were made neutropenic with cyclophosphamide. Lungs of I− mice were inoculated intranasally with bacterial suspensions of 107 CFU/mL; a higher inoculum of 109 CFU/mL was required to induce infection in I+ mice. Single daily doses of TZD simulating human ELF exposures after doses of 200 mg q24h were determined in both I+ (40 mg/kg) and I− (32 mg/kg) models. Three hours after inoculation, human-simulated doses of TZD were administered q24h for up to 72 hours while control mice were vehicle dosed. A group of control and another of treatment (n = 6) per isolate were sacrificed at 24, 48, or 72 hours for lung harvest. Bacterial densities were determined by quantitative culture and averaged across all isolates. Mice that succumbed to infection before the scheduled time of sacrifice were included in the next group due for sacrifice. Changes in log10 CFU/lungs at 24 hours were compared with 0 hour controls.ResultsThe average bacterial burdens at 0 hour were 5.86 ± 0.21 and 8.10 ± 0.24 log10 CFU/lungs among I− and I+ mice, respectively. At 24 hours, average burdens in control mice were comparable among I− and I+ mice at 7.91 ± 0.62 and 9.01 ± 0.69 log10CFU/lungs, respectively. Mean changes in bacterial density are reported in the table. No I+ control mice survived past 48 hours.Change in Log10 CFU/Lungs (Mean ± SD)I−I+24 hoursControl2.06 ± 0.620.91 ± 0.69TZD−1.18 ± 0.58−1.23 ± 0.8148 hoursControl2.54 ± 0.310.61 ± 0.17TZD−1.99 ± 0.90−2.17 ± 0.8472 hoursControl2.85 ± 0.60NDTZD−2.78 ± 0.74−3.64 ± 1.03ND, no data.ConclusionHuman-simulated ELF exposures of TZD demonstrated substantial and sustained efficacy in both I− and I+ murine models of pneumonia. These preclinical data utilizing clinically achievable bronchopulmonary exposures suggest that the efficacy of TZD for treatment of MRSA lung infections is not compromised by neutropenic status of the host. Further validation of these findings in patients is warranted.Disclosures D. P. Nicolau, Merck: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Speaker honorarium.

1153. UV-C Technology Is an Effective Adjunct to Terminal Cleaning in Environmental Pathogen Reduction in a Tertiary Pediatric Hospital

BackgroundEffective environmental surface cleaning plays a vital role in reducing transmission of hospital-acquired infections. There remains a paucity of data in the pediatric literature regarding environmental pathogen reduction utilizing UV-C light. The objective of this study was to evaluate the reduction of environmental pathogens using UV-C light (Clorox Optimum-UV) as an adjunct to terminal cleaning in a free-standing tertiary pediatric hospital.MethodsUpon patient discharge, a subset of patient rooms were tested for pathogens. Surface swabs were collected from high touch surfaces (call button, telemetry monitor, door handle, flush handle of toilet, faucet, bed rail, phone, keyboard pad, mouse, side table, dresser, and light switch). After terminal cleaning of the room, per hospital protocol the Clorox Optimum-UV completed one or two cycles of 5 minutes each depending on the dimensions of the room. Post-UV-C surface swabs were obtained from the same high touch areas in the room. Total colony count was reported from each of the surfaces swabbed. Swabs were streaked onto non-selective agar and incubated at 30-35oC for 72–96 hours. Mean plate colony count was determined manually and reported as CFU/swab. Data analysis was performed in Minitab 18.1. Fisher least significant difference (LSD) test was used to describe the difference between total bacterial counts at each time point (Pre-clean: dirty room, Post-clean: pre-UV-C/post-terminal clean, Post-UV: post UV-C light cycle).ResultsMean total colony counts prior to cleaning the room was 92.3 CFU (33 surfaces), Pre-UV-C light 45.6 CFU and post-UV-C light 5.8 CFU (64 surfaces). Total bacterial counts are represented in Graphs 1 and 2. Upon multivariate analysis, the time the sample was taken (preclean, postclean, or post-UV) was the single explanatory variable for the differences seen in the means of total bacterial counts (P = 0).ConclusionOur study demonstrates that UV-C disinfection is a highly effective adjunctive cleaning method with standard terminal cleaning to reduce bacterial burden from environmental surfaces.Graph 1: Total Bacterial Counts (CFU) at each timepoint of surface sampling.Graph 2: Total Bacterial Counts (CFU) with 95% Confidence Intervals at each timepoint of surface sampling.Disclosures A. Lucas, Clorox: Research Contractor, Grant recipient. M. Nayakwadi Singer, Clorox: Grant Investigator, Grant recipient.

1130. Low Risk of Pneumocystis jiroveci Pneumonia in Patients With Waldenstrom’s Macroglobulinemia on Ibrutinib

BackgroundIbrutinib is a Bruton’s tyrosine kinase inhibitor that is FDA approved for the treatment of chronic lymphocytic leukemia (CLL), mantle cell lymphoma, marginal zone lymphoma, and Waldenstrom’s macroglobulinemia (WM). Fungal infections including Pneumocystis jiroveci pneumonia (PCP) are increasingly reported in patients with CLL and lymphoma on ibrutinib possibly due to the off-target effect of ibrutinib on the adaptive immune system. Whether this increased risk is due to the effect of ibrutinib alone or in combination with immune dysregulation due to underlying malignancy is unknown. The purpose of this study was to assess the incidence of PCP in patients with WM on ibrutinib therapy.MethodsA retrospective cohort study was performed of all patients with WM who initiated ibrutinib monotherapy at Dana-Farber Cancer Institute between July 1, 2015 and January 30, 2018. Baseline characteristics, laboratory parameters, previous and concomitant malignancy treatment regimens, and antimicrobial medications were collected by chart review. Patients were followed until April 1, 2018 for the development of PCP.ResultsThere were a total of 106 patients with WM on ibrutinib during the study period. Sixty-one (58%) were male, and the median age at initiation of ibrutinib was 69 years (range 43 – 89). Forty-six patients (43%) received prior therapy for WM, with a median of two previous treatment courses (range 1–6). Fourteen patients (13%) were on PCP prophylaxis for a combined duration of 8 person-years. No cohort patient developed PCP during the study period, which included 146 person-years of ibrutinib exposure. Three patients (3%) died due to disease progression (n = 2) and E. coli sepsis (n = 1).ConclusionPatients with WM on ibrutinib monotherapy appear to have a different infectious risk profile than patients with CLL or lymphoma and do not have a high risk of developing PCP. These data suggest that PCP prophylaxis is likely not beneficial for patients with WM on ibrutinib.Disclosures M. P. Cheng, Royal College of Physicians and Surgeons of Canada: Member, Salary. S. P. Hammond, Merck: Investigator, Research support. J. J. Castillo, Pharmacyclics: Consultant and Grant Investigator, Consulting fee and Research grant. N. C. Issa, GSK: Investigator, Research grant. Merck: Investigator, Research grant. Akros Pharma: Consultant, Consulting fee.