An ASP is mandated for all hospitals and requires extensive resources with multidisciplinary collaboration. We measured the impact of implementing real-time decision support software (ILUM Insight) within our ASP.Our ASP has relied on prior authorization since 2002 and focused audit and feedback since 2015. In August 2021 we implemented to bring actionable data to front-line stewards. ILUM provides real-time notifications, organizes communications, and tracks patient-and provider-level data. We hypothesized that ILUM would increase the efficiency of ASP workflow and result in decreased antimicrobial utilization. We compared data 6 months before (8/20 – 1/21) and after (8/21 – 1/22) implementation. There were no significant staffing changes during either period.Fig 1. With increased ILUM usage, the number of interventions made by our ASP increased while missed opportunities decreased . During the same time period, ASP communications rose from 205 to 1200 per month. Comparing pre- and post-implementation periods, antimicrobial days of therapy (DOT) per 1,000 patient days (PD) decreased by 14.5% from a median of 969 to 846 per month . Antimicrobial expenditures were decreased by a median 21% per month during the post-intervention period compared to baseline. Among patients prescribed antimicrobials during an index admission, 30-day re-admissions decreased from 330 to 262 and re-admissions associated with re-ordering of antimicrobials decreased from 235 to 182 .Existing notifications within ILUM were tailored to local practices, including alerts with intervention for positive blood cultures, antibiotic de-escalation, and bug-drug mismatches. New notifications were built for restricted antimicrobials, antibiotic timeouts, and MRSA screening. ASP pharmacists and physicians received training in July and November, respectively. A breakdown of all notifications received during the post-implementation period is provided in Custom-designed, task-specific software improves the efficiency of daily ASP workflow and significantly decreased antimicrobial utilization without the need for additional ASP team members.Ryan K. Shields, PharmD, MS, Infectious Disease Connect: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Roche: Grant/Research Support J Ryan Bariola, MD, Infectious Disease Connect: Salary support|Merck: Grant/Research Support Caley Yakemowicz, n/a, Infectious Disease Connect: Employee Courtney Simonick, n/a, Infectious Disease Connect: Stocks/Bonds Riaan Erwee, na, Infectious Disease Connect: Employee Erin K. McCreary, PharmD, Infectious Disease Connect: Advisor/Consultant Rima Abdel-Massih, MD, Infectious Disease Connect: Co founder and Chief Medical Officer|Infectious Disease Connect: Ownership Interest.


Desirability of outcome ranking (DOOR) uses an ordinal ranking system to evaluate global outcomes in clinical trial participants by incorporating safety and efficacy assessments into a single endpoint. In this study, we developed and applied a DOOR endpoint for cIAI clinical trials.We reviewed 10 Phase 3 noninferiority trials for cIAI with electronic patient-level data (n=5473 participants) submitted to the FDA between 2005-2021. Extending previous work [CID. 2019:68(10):1691-8)], we developed an expanded cIAI-specific DOOR endpoint based on clinically meaningful events captured in trial datasets and those that were unique to patients with cIAI. Using this DOOR endpoint, we assigned each participant a DOOR rank, estimated the probability that a participant in the study treatment arm in each trial would have a more desirable DOOR rank than if assigned to the comparator arm, and analyzed individual components of clinical experience in each trial.Based on analysis of available data, we noted heterogeneity in definitions of “indeterminate” clinical outcomes, and significant diversity and increased incidence of infectious complications (ICs), serious adverse events (SAEs), and surgical/percutaneous procedures in participants without clinical cure. These informed the expansion of the DOOR endpoint for cIAI to include clinical efficacy outcomes, ICs, SAEs, and additional procedures (Table 1). The DOOR distributions between treatment and comparator arms in all 10 trials were similar. DOOR probability estimates for the 10 trials ranged from 44.5% to 50.3% but were not nominally statistically significant. Component analyses in two trials showed that the study treatment was nominally statistically inferior to the comparator with regard to SAEs and clinical failure, respectively .Trial 1 has no significant differences between the treatment arms in the component analysis (A). The study treatment arm was shown to be nominally statistically inferior for SAEs in Trial 2 (B) and for clinical failure in Trial 3 (C).We developed a cIAI-specific DOOR endpoint to better elucidate the events that participants experienced in these trials. The component analysis allowed more nuanced evaluation of the factors that contributed to the composite DOOR probability estimate and provided a visual display of the risk-benefit assessment of a study treatment vs. the comparator. Our study was limited by its retrospective approach and trial design heterogeneity.Deborah Collyar, B.Sci, Apellis Pharmaceuticals, Inc.: Advisor/Consultant|Kinnate Biopharma: Advisor/Consultant|M2GEN: Advisor/Consultant|Maxis Clinical Sciences: Advisor/Consultant|Parexel: Honoraria|Pfizer: Honoraria|Roundtable Analytics, Inc.: Ownership Interest Sarah B. Doernberg, MD, MAS, Basilea: Clincal events committee|Genentech: Advisor/Consultant|Gilead: Grant/Research Support|Regeneron: Grant/Research Support|Shinogi: Clincal events committee Scott R. Evans, Ph.D., M.S., Abbvie: DSMB|Akouos: DSMB|Apellis: DSMB|AstraZeneca: Advisor/Consultant|Atricure: Advisor/Consultant|Becton Dickenson: Advisor/Consultant|Breast International Group: DSMB|Candel: DSMB|ChemoCentrix: Advisor/Consultant|Clover: DSMB|DayOneBio: DSMB|DeGruyter: Editor|Duke University: DSMB|Endologix: Advisor/Consultant|FHI Clinical: DSMB|Genentech: Advisor/Consultant|Horizon: Advisor/Consultant|International Drug Development Institute: Advisor/Consultant|Janssen: Advisor/Consultant|Lung Biotech: DSMB|Neovasc: Advisor/Consultant|NIH: Grant/Research Support|Nobel Pharma: Advisor/Consultant|Nuvelution: DSMB|Pfizer: DSMB|Rakuten: DSMB|Roche: DSMB|Roivant: Advisor/Consultant|SAB Biopharm: DSMB|SVB Leerink: Advisor/Consultant|Takeda: DSMB|Taylor & Francis: Book royalties|Teva: DSMB|Tracon: DSMB|University of Penn: DSMB|Vir: DSMB Thomas L. Holland, MD, Aridis: Advisor/Consultant|Lysovant: Advisor/Consultant Henry Chambers, MD, Merck: DSMB member|Merck: Stocks/Bonds|Moderna: Stocks/Bonds Vance G. Fowler, Jr, MD, MHS, Affinergy: Grant/Research Support|Affinergy: Honoraria|Affinium: Honoraria|Amphliphi Biosciences: Honoraria|ArcBio: Stocks/Bonds|Basilea: Grant/Research Support|Basilea: Honoraria|Bayer: Honoraria|C3J: Honoraria|Cerexa/Forest/Actavis/Allergan: Grant/Research Support|Contrafect: Grant/Research Support|Contrafect: Honoraria|Cubist/Merck: Grant/Research Support|Debiopharm: Grant/Research Support|Deep Blue: Grant/Research Support|Destiny: Honoraria|Genentech: Grant/Research Support|Genentech: Honoraria|Integrated Biotherapeutics: Honoraria|Janssen: Grant/Research Support|Janssen: Honoraria|Karius: Grant/Research Support|Medicines Co.: Honoraria|MedImmune: Grant/Research Support|MedImmune: Honoraria|NIH: Grant/Research Support|Novartis: Grant/Research Support|Novartis: Honoraria|Pfizer: Grant/Research Support|Regeneron: Grant/Research Support|Regeneron: Honoraria|Sepsis diagnostics: Sepsis diagnostics patent pending|UpToDate: Royalties|Valanbio: Stocks/Bonds Sumathi Nambiar, MD MPH, Johnson and Johnson: Stocks/Bonds Helen W. Boucher, MD, American Society of Microbiology: Honoraria|Elsevier: Honoraria|Sanford Guide: Honoraria.


The epidemiology of antibiotic-resistant pathogens guides antimicrobial therapy for bacterial bloodstream infections (BSI). We describe changes in antimicrobial-resistant BSI pathogens over time within the US Military Health System (MHS), which prospectively captures clinical and microbiological data from both retired and active-duty US Uniformed service members and their beneficiaries.in vitro resistance to three classes of antibiotics: carbapenems, extended-spectrum cephalosporins, and fluoroquinolones.The study population included MHS beneficiaries with blood cultures positive for any bacterial pathogens (Jan 2010 – Dec 2019). Microbiological data were obtained from the Navy and Marine Corps Public Health Center and antibiotic resistance was interpreted using CLSI breakpoints corresponding to collection year. Blood contaminants were excluded. Difficult to treat resistance (DTR) was defined in Gram-negative bacteria (GNB) as isolates with Streptococcus/Enterococcus spp. (33%), Staphylococcus aureus (20%), and non-lactose fermenting GNB . The rate of LFGNB BSI increased from 7.57 per 100,000 beneficiaries in 2010 to 8.42 in 2019 (peak of 8.83 in 2016), resulting in an increase of 11.3% during the study period . Rates of BSI attributed to Streptococcus/Enterococcus spp., S. aureus, and NLGNB decreased 26%, 29%, and 45%, respectively, over the study period. The average annual rates of methicillin-resistant S. aureus, vancomycin-resistant Enterococcus spp., and DTR GNB BSI were 1.30, 0.25, and 0.05 per 100,000 beneficiaries, respectively. Over the study period, these rates decreased 58.3%, 72.4% and 24.2%, respectively.The 15 most frequent bacterial pathogens, representing 15,358 BSI episodes from 12,749 individuals, were subcategorized in four groups based on shared BSI clinical features. Lactose-fermenting GNB (LFGNB) were most common, accounting for 42% of BSI pathogens, following by Pseudomonas aeruginosa and Acinetobacter spp.) decreased. The burden of DTR GNB BSI also decreased, indicating that first-line antibiotics remain clinically available for most patients with BSI.LFGNB BSI numerically increased over time while NLGNB BSI (e.g., John H. Powers, III, MD, Arrevus: Advisor/Consultant|Eicos: Advisor/Consultant|Evofem: Advisor/Consultant|Eyecheck: Advisor/Consultant|Gilead: Advisor/Consultant|GlaxoSmithKline: Advisor/Consultant|OPKO: Advisor/Consultant|Resolve: Advisor/Consultant|Romark: Advisor/Consultant|SpineBioPharma: Advisor/Consultant|UTIlity: Advisor/Consultant|Vir: Advisor/Consultant.


The combination of CZA-ATM is frequently used to treat patients with metallo-β-lactamase (MBL)-producing Enterobacterales (EB) infections, but its safety has not been established in controlled trials. This phase 1 study evaluated the safety of the optimal CZA-ATM regimens identified in the hollow fiber infection model of MBL-producing EB (PMID: 32464664).Table 1). Study safety was monitored by assessments of adverse events (AEs), vital signs, and clinical laboratory safety tests.The phase I, open-label, single center study enrolled healthy adults aged 18-45 years (NCT03978091). Subjects were sequentially assigned to 1 of 6 Cohorts and administered investigational product(s) (IP) for 7 days . The most common IP related investigation AEs were ALT/AST elevations (35%) with 94% occurring in subjects who received ATM alone or in combination. The incidence of ALT/AST elevation AEs in the combination Cohorts were comparable to the ATM alone Cohorts. In the ATM single IP Cohorts, 3 subjects experienced severe ALT/AST elevation AEs, which halted the study. All subjects who experienced ALT/AST elevations were asymptomatic, had no other clinical findings suggestive of liver injury, and all resolved without intervention. Most other IP related AEs were of mild severity and similar across Cohorts except prolonged prothrombin time (PT) AEs, which was more frequent in combination Cohorts.Of 48 subjects enrolled, 50% were female and 60% were Black. The mean (SD) age was 33.5 (6.2) years and mean (SD) weight was 75.7 (12.1) kg. The number of subjects who had ≥ 1 AE and experienced ≥ 1 IP related AE was 46 (96%) and 41 (85%), respectively. Frequency of IP related AEs by MedDRA system organ class, severity, and Cohort are shown in Clinicians should only consider using CZA-ATM when the benefits outweigh the risks. If CZA-ATM is prescribed, clinicians are advised to monitor for hepatic injury. Close monitoring of coagulation parameters may also be prudent with CZA-ATM. Future comparator-controlled randomized clinical trials are required to better define the safety and efficacy of the CZA-ATM regimens.Thomas Lodise, Jr., Pharm.D., PhD, BioFire Diagnostics: Grant/Research Support|cidara: Advisor/Consultant|cidara: Honoraria|Entasis: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support|Paratek: Advisor/Consultant|Shionogi: Advisor/Consultant|Spero: Advisor/Consultant|Venatrox: Advisor/Consultant J Nicholas O'Donnell, Pharm.D., Merck & Co, Inc: Grant/Research Support|Paratek Pharmaceuticals: Grant/Research Support Stephen Balevic, MD, Purdue Pharma: Grant/Research Support|UCB: Advisor/Consultant Jeffrey Guptill, MD, argenx: Stocks/Bonds Vance G. Fowler, Jr, MD, MHS, Affinergy: Grant/Research Support|Affinergy: Honoraria|Affinium: Honoraria|Amphliphi Biosciences: Honoraria|ArcBio: Stocks/Bonds|Basilea: Grant/Research Support|Basilea: Honoraria|Bayer: Honoraria|C3J: Honoraria|Cerexa/Forest/Actavis/Allergan: Grant/Research Support|Contrafect: Grant/Research Support|Contrafect: Honoraria|Cubist/Merck: Grant/Research Support|Debiopharm: Grant/Research Support|Deep Blue: Grant/Research Support|Destiny: Honoraria|Genentech: Grant/Research Support|Genentech: Honoraria|Integrated Biotherapeutics: Honoraria|Janssen: Grant/Research Support|Janssen: Honoraria|Karius: Grant/Research Support|Medicines Co.: Honoraria|MedImmune: Grant/Research Support|MedImmune: Honoraria|NIH: Grant/Research Support|Novartis: Grant/Research Support|Novartis: Honoraria|Pfizer: Grant/Research Support|Regeneron: Grant/Research Support|Regeneron: Honoraria|Sepsis diagnostics: Sepsis diagnostics patent pending|UpToDate: Royalties|Valanbio: Stocks/Bonds henry chambers, MD, Merck: DSMB member|Merck: Stocks/Bonds|Moderna: Stocks/Bonds.


In vitro-in vivo discordance in the activity of β-lactams against MBL-producing Enterobacterales has been described. This discordance is likely attributed to the supra-physiologic zinc level in the in vitro testing media, which facilitates the bicyclic β-lactam ring hydrolysis. In this study, we compared the outcome of empirical non-MBL-active β-lactam therapy (carbapenems and ceftazidime/avibactam) and MBL-active β-lactam therapy (ceftazidime/avibactam plus aztreonam) among patients with bloodstream infections due to NDM-producing Klebsiella pneumoniae. Validation of the efficacy of carbapenem in a murine septicemia model was conducted. In vitro susceptibility testing conditions were altered to better predict the in vivo outcome.A retrospective observational study of patients admitted to hospitals in Italy. The primary outcome was 14-day all-cause mortality. Cox regression analysis was performed to evaluate primary outcome. Kaplan Meier survival and log-rank test were used to compare 14-day mortality between patient’s cohorts. Septicemia was induced in mice via intraperitoneal inoculation with the isolates retrieved from the patients then clinical exposure of meropenem  was given for 2 days. Survival was recorded for 4 days and compared with sham controls. Unbound zinc levels were measured in human and infected mice plasma. MEM MICs were determined in Mueller Hinton Broth (MHB) and MHB adjusted to the physiologic zinc levels.Of the patients identified, 29 received empirical non-MBL-active β-lactams for median duration 4 days while 29 received MBL-active β-lactams. The 14-day mortality rate was 21% in the non-MBL-active group vs 14% in the MBL-active group (P = 0.73) and survival patterns were not significantly different . Cox regression showed that use of non-MBL-active therapy was not associated with significantly increased 14-day mortality . MEM treatment resulted in protection from mortality in mice . MEM MICs in zinc-adjusted MHB were 1- to > 16-fold lowered relative to MICs in MHB ( ≥ 64 mg/L).Our data provide foundational support to help establish PK/PD relationships using MICs derived in physiologic zinc levels which may better predict β-lactam therapy outcome.Kamilia Abdelraouf, PhD, Evopoint Biosciences Co., Ltd: Grant/Research Support|Venatorx Pharmaceuticals, Inc.: Grant/Research Support Christian M. Gill, PharmD, Everest Medicines, Shionogi, Cepheid: Grant/Research Support Matthew Gethers, PhD, Thermo Fisher: Employee Marco Falcone, MD, PhD, GILEAD: Grant/Research Support|GSK: Honoraria|MENARINI: Advisor/Consultant|MENARINI: Grant/Research Support|MSD: Honoraria|PFIZER: Honoraria|SHIONOGI: Grant/Research Support Francesco Menichetti, n/a, Aneglini: Advisor/Consultant|Aneglini: Board Member|Aneglini: Grant/Research Support|Aneglini: Honoraria|Astellas: Advisor/Consultant|Astellas: Honoraria|Becton: Advisor/Consultant|Becton: Honoraria|bioMérieux: Advisor/Consultant|bioMérieux: Honoraria|Biotest: Advisor/Consultant|Biotest: Board Member|Biotest: Honoraria|Bristol-Myers Squibb: Advisor/Consultant|Bristol-Myers Squibb: Honoraria|Correvio: Advisor/Consultant|Correvio: Speaker honoraria|Dickinson: Advisor/Consultant|Dickinson: Honoraria|Gilead: Advisor/Consultant|Gilead: Grant/Research Support|Janssen: Advisor/Consultant|Janssen: Honoraria|MSD: Advisor/Consultant|MSD: Speaker honoraria|Nordic pharma: Board Member|Nordic pharma: Honoraria|Pfizer: Advisor/Consultant|Pfizer: Honoraria|Shionogi: Advisor/Consultant|Shionogi: Honoraria|ViiV: Advisor/Consultant|ViiV: Honoraria David P. Nicolau, PharmD, Shionogi: Grant/Research Support.


Respiratory syncytial virus (RSV) is the major cause of lower respiratory tract infection (LRTI) and hospitalization in infants. In two global pivotal placebo-controlled studies, nirsevimab, a monoclonal antibody to the RSV prefusion (F) protein with extended half-life, reduced medically attended (MA) RSV LRTI versus placebo throughout the RSV season (MELODY (Primary Cohort)/Study 3 (Proposed Dose) Pool, 79.5% efficacy). Here we summarize resistance analyses of all RT-PCR-confirmed RSV isolates from healthy term and preterm infants through 150 days post dose.Infants were randomized 2:1 to receive one intramuscular injection of nirsevimab or placebo, prior to their first RSV season. RT-PCR-confirmed RSV isolates were reflexed for genotypic analyses of RSV F and phenotypic analyses of identified substitutions in a recombinant RSV neutralization susceptibility assay.In the pooled proposed dose analysis of Study 3 (50 mg nirsevimab if < 5 kg at dosing) and MELODY , no subject with MA RSV LRTI had an RSV isolate containing nirsevimab resistance-associated substitutions in either treatment group . In Study 3 (50 mg nirsevimab if ≥5 kg at dosing), 2/18 subjects in the nirsevimab group and 0/20 subjects in the placebo group with MA RSV LRTI had an RSV isolate harbouring nirsevimab binding site substitutions I64T+K68E+I206M+Q209R (>447-fold) or N208S (>387-fold) that conferred reduced susceptibility to nirsevimab neutralization . Subjects with RSV isolates harboring F protein sequence variations that maintained susceptibility to nirsevimab neutralization were balanced between treatment groups with no association with RSV disease severity. No subjects with non-protocol defined MA RSV LRTI cases or hospitalization due to any RSV respiratory illness had an RSV isolate conferring nirsevimab resistance.Lack of nirsevimab resistance following immunization at the proposed dose supports efficacy and neutralization activity of nirsevimab against both RSV A and B strains throughout the RSV season.Michael E. Abram, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Bahar Ahani, BSC, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds David E. Tabor, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Fiona Fernandes, PhD, AstraZeneca: Stocks/Bonds Deidre Wilkins, BSC, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Anastasia A. Aksyuk, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Kevin M. Tuffy, MS, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Hong Ji, BSc, AstraZeneca: Stocks/Bonds Christine Blaze, BSc, AstraZeneca: Stocks/Bonds Tyler Brady, MS, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Pamela Griffin, MD, AstraZeneca: Stocks/Bonds Amanda Leach, MD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Tonya L. Villafana, PhD, MPH, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Mark T. Esser, PhD, AstraZeneca: Stocks/Bonds.


Details of correction: correct grant no. in acknowledgementExisting text: “The Deanship of Scientific Research (DSR) at King Abdulaziz University (KAU), Jeddah, Saudi Arabia, has funded this Project Under grant no (G: 683-253-3443).”Corrected text should read: “The Deanship of Scientific Research (DSR) at King Abdulaziz University (KAU), Jeddah, Saudi Arabia, has funded this Project Under grant no (G: 683-253-1443).”


Symptoms during acute COVID-19 can limit daily activities and delay return to work and school. Little is known about the association between SARS-CoV-2 burden in either the upper airway or plasma and the duration of COVID-19 symptoms.ACTIV-2/A5401 is a platform trial for COVID-19 treatments in non-hospitalized symptomatic adults enrolled within 10 days of symptom onset. We included participants randomized to placebo from August 2020 to July 2021. Participants self-reported severity of 13 symptoms daily from day 0 (baseline) to 28 as Absent 0, Mild 1, Moderate 2, Severe 3; total symptom score was calculated as the sum of all scores. Anterior nasal (AN) and plasma SARS-CoV-2 RNA levels at day 0 were measured with a quantitative qPCR assay. The relationship between day 0 RNA and time to symptom improvement or resolution  was evaluated using proportional hazards regression adjusted for time from symptom onset. Time to resolution of distinct symptoms was also assessed.10 copies/ml  and plasma RNA was detectable in 19% (91/476). Detectable plasma RNA at day 0, but not AN RNA, was associated with more severe symptoms at day 0 . Both high AN  and detectable plasma RNA  at day 0 predicted delayed symptom improvement. High AN RNA at day 0 also predicted a delay in symptom resolution . Both high AN RNA and detectable plasma RNA levels predicted delays in the resolution of cough and shortness of breath. Detectable plasma RNA also predicted delayed body pain resolution.Among 570 participants randomized to placebo, median age was 48 years, 51% were female, and median time since symptom onset at baseline was 6 days; 7% had prior COVID-19 vaccination. At day 0, AN RNA was detectable in 80% with a median of 4.1 logCOVID-19 outpatients with high AN or detectable plasma SARS-CoV-2 RNA at day 0 are more likely to have prolonged symptoms, particularly respiratory symptoms. Additional studies are needed to determine whether the decline in viral load with early treatment impacts symptom duration.Kara W. Chew, M.D., M.S., Merck Sharp & Dohme: Grant/Research Support|Pardes Bioscences: Advisor/Consultant Joseph J. Eron, MD, GSK: Advisor/Consultant|Merck: Advisor/Consultant Eric S. Daar, M.D., Gilead: Advisor/Consultant|Gilead: Grant/Research Support|Merck: Advisor/Consultant|ViiV: Advisor/Consultant|ViiV: Grant/Research Support David A. Wohl, M.D., Gilead: Advisor/Consultant|Gilead: Grant/Research Support|Lilly: Grant/Research Support|ViiV: Advisor/Consultant|ViiV: Grant/Research Support Judith S. Currier, M.D., MSc, Merck: Advisor/Consultant Davey M. Smith, M.D., M.A.S., Arena Pharmaceuticals: Advisor/Consultant|Bayer Pharmaceuticals: Advisor/Consultant|Brio Clinical.: Advisor/Consultant|Fluxergy: Advisor/Consultant|Kiadis: Advisor/Consultant|Linear Therapies: Advisor/Consultant|Matrix BioMed: Advisor/Consultant|Model Medicines: Advisor/Consultant|Signant Health: Advisor/Consultant|VxBiosciences: Advisor/Consultant Jonathan Z. Li, MD, MMSc, Abbvie: Advisor/Consultant|Merck: Grant/Research Support.


SUL-DUR is a β-lactam/β-lactamase inhibitor combination in development for the treatment of ABC infections, which are often severe and associated with substantial mortality. PPK, PTA, and clinical PK/PD analyses were conducted using all available PK and efficacy data to support SUL-DUR dose selection.PPK analyses were performed using PK data from 373 subjects, including 110 patients who received SUL-DUR and underwent PK sampling in the pivotal Phase 3 (ATTACK) trial. SUL-DUR concentrations in epithelial lining fluid (ELF) from healthy subjects were utilized to predict SUL-DUR ELF concentrations in Phase 3 patients. Covariate analyses evaluated the impact of demographic factors on PK exposures. The PPK model, non-clinical PK/PD data, and in vitro surveillance data were used to assess the PTA by MIC in simulated patients with ABC infections. Clinical PK/PD relationships were assessed using dichotomous and time-to-event efficacy endpoints from the ATTACK trial.10. No relationships were observed between PK/PD indices and efficacy endpoints, consistent with most patients achieving SUL and DUR exposures above nonclinical PK/PD targets for efficacy.Two-compartment models with linear kinetics best characterized SUL and DUR PK. Consistent with high renal clearance of SUL-DUR, dose adjustments are needed in patients with renal impairment or augmented renal function. Body weight, site of infection, and East Asian region  were statistically significant covariates in the PPK analysis but were not clinically relevant. No other statistical or clinically relevant covariates were identified. As shown in Figures A and B for plasma and ELF, respectively, the PTA was ≥ 90% for pathogens with an MIC ≤ 4 µg/mL across renal function categories in simulated patients, using PK/PD targets associated with a 1-log killPercent PTA by MIC on Day 1 based on the assessment of sulbactam %T>MIC ≥ 50% and durlobactam AUC:MIC ratio ≥ 10 targets and free-drug plasma (A) and total-drug ELF (B) exposures among simulated patients by CLcr group after administration of sulbactam 1 g/ durlobactam 1 g IV q6h and dosing regimens adjusted for renal impairment and augmented renal functionThe simulated plasma and ELF exposures yielded a high PTA, which when combined with the favorable efficacy and safety findings from ATTACK (abstract #1266378), support a dose of 1.0 g sulbactam/1.0 g durlobactam via a 3-hour infusion, every 6 hours in patients with normal renal function and renal function-based dose adjustments.Sujata M. Bhavnani, PharmD; MS; FIDSA, Adagio Therapeutics, Inc.: Grant/Research Support|Amplyx Pharmaceuticals, Inc.: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc.: Grant/Research Support|B. Braun Medical Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Bravos Biosciences: Ownership Interest|Celdara Medical LLC: Grant/Research Support|Cidara Therapeutics Inc.: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc.: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Evopoint Biosciences Co.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|ICPD: Ownership Interest|ICPD Biosciences, LLC.: Ownership Interest|ICPD Holdings: Ownership Interest|ICPD Technologies: Ownership Interest|Insmed Inc.: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Lassen Therapeutics: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Menarini Ricerche S.p.A.: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novartis Pharmaceuticals Corp.: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|PureTech Health: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|TauRx Therapeutics: Grant/Research Support|Tetraphase Pharmaceuticals: Grant/Research Support|tranScrip Partners: Grant/Research Support|Utility Therapeutics: Grant/Research Support|Valanbio Therapeutics, Inc.: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support Sujata M. Bhavnani, PharmD; MS; FIDSA, Adagio Therapeutics, Inc.: Grant/Research Support|Amplyx Pharmaceuticals, Inc.: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc.: Grant/Research Support|B. Braun Medical Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Bravos Biosciences: Ownership Interest|Celdara Medical LLC: Grant/Research Support|Cidara Therapeutics Inc.: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc.: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Evopoint Biosciences Co.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|ICPD: Ownership Interest|ICPD Biosciences, LLC.: Ownership Interest|ICPD Holdings: Ownership Interest|ICPD Technologies: Ownership Interest|Insmed Inc.: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Lassen Therapeutics: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Menarini Ricerche S.p.A.: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novartis Pharmaceuticals Corp.: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|PureTech Health: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|TauRx Therapeutics: Grant/Research Support|Tetraphase Pharmaceuticals: Grant/Research Support|tranScrip Partners: Grant/Research Support|Utility Therapeutics: Grant/Research Support|Valanbio Therapeutics, Inc.: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support Sujata M. Bhavnani, PharmD; MS; FIDSA, Adagio Therapeutics, Inc.: Grant/Research Support|Amplyx Pharmaceuticals, Inc.: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc.: Grant/Research Support|B. Braun Medical Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Bravos Biosciences: Ownership Interest|Celdara Medical LLC: Grant/Research Support|Cidara Therapeutics Inc.: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc.: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Evopoint Biosciences Co.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|ICPD: Ownership Interest|ICPD Biosciences, LLC.: Ownership Interest|ICPD Holdings: Ownership Interest|ICPD Technologies: Ownership Interest|Insmed Inc.: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Lassen Therapeutics: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Menarini Ricerche S.p.A.: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novartis Pharmaceuticals Corp.: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|PureTech Health: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|TauRx Therapeutics: Grant/Research Support|Tetraphase Pharmaceuticals: Grant/Research Support|tranScrip Partners: Grant/Research Support|Utility Therapeutics: Grant/Research Support|Valanbio Therapeutics, Inc.: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support Christopher M. Rubino, PharmD, Adagio Therapeutics: Grant/Research Support|Amplyx Pharmaceuticals, Inc.: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc.: Grant/Research Support|B. Braun Medical Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Bravos Biosciences: Ownership Interest|Celdara Medical LLC: Grant/Research Support|Cidara Therapeutics Inc.: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc.: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Evopoint Biosciences Co.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|ICPD: Ownership Interest|ICPD Biosciences, LLC.: Ownership Interest|ICPD Holdings: Ownership Interest|ICPD Technologies: Ownership Interest|Insmed Inc.: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Lassen Therapeutics: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Menarini Ricerche S.p.A.: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novartis Pharmaceuticals Corp: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|PureTech Health: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|TauRx Therapeutics: Grant/Research Support|Tetraphase Pharmaceuticals: Grant/Research Support|tranScrip Partners: Grant/Research Support|Utility Therapeutics: Grant/Research Support|Valanbio Therapeutics, Inc.: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support Jeffrey P. Hammel, MS, Adagio Therapeutics, Inc.: Grant/Research Support|Amplyx Pharmaceuticals, Inc.: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc.: Grant/Research Support|B. Braun Medical Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Celdara Medical LLC: Grant/Research Support|Cidara Therapeutics Inc.: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc.: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Evopoint Biosciences Co.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|Insmed Inc.: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Lassen Therapeutics: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Menarini Ricerche S.p.A.: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novartis Pharmaceuticals Corp.: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|PureTech Health: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|TauRx Therapeutics: Grant/Research Support|Tetraphase Pharmaceuticals: Grant/Research Support|tranScrip Partners: Grant/Research Support|Utility Therapeutics: Grant/Research Support|Valanbio Therapeutics, Inc.: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support Anthony P. Cammarata, M.S., Adagio Therapeutics, Inc: Grant/Research Support|Amplyx Pharmaceuticals, Inc.: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc: Grant/Research Support|B. Braun Medical Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Celdara Medical LLC: Grant/Research Support|Cidara Therapeutics Inc: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Evopoint Biosciences Co: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|Insmed Inc.: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Lassen Therapeutics: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Menarini Ricerche S.p.A.: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novartis Pharmaceuticals Corp.: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|PureTech Health: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|TauRx Therapeutics: Grant/Research Support|Tetraphase Pharmaceuticals: Grant/Research Support|tranScrip Partners: Grant/Research Support|Utility Therapeutics: Grant/Research Support|Valanbio Therapeutics, Inc.: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support Kajal Larson, PhD, Entasis Therapeutics: Employee Kathryn Liolios, MA, Adagio Therapeutics, Inc.: Grant/Research Support|Amplyx Pharmaceuticals, Inc.: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc.: Grant/Research Support|B. Braun Medical Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Celdara Medical LLC: Grant/Research Support|Cidara Therapeutics Inc.: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc.: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Evopoint Biosciences Co.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|Insmed Inc.: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Lassen Therapeutics: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Menarini Ricerche S.p.A.: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novartis Pharmaceuticals Corp.: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|PureTech Health: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|TauRx Therapeutics: Grant/Research Support|Tetraphase Pharmaceuticals: Grant/Research Support|tranScrip Partners: Grant/Research Support|Utility Therapeutics: Grant/Research Support|Valanbio Therapeutics, Inc.: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support Sarah McLeod, PhD, Entasis Therapeutics: Employee Alita Miller, PhD, Entasis Therapeutics: Employee Paul G. Ambrose, PharmD; MS; FIDSA, Adagio Therapeutics, Inc.: Grant/Research Support|Amplyx Pharmaceuticals, Inc.: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc.: Grant/Research Support|B. Braun Medical Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Bravos Biosciences: Ownership Interest|Celdara Medical LLC: Grant/Research Support|Cidara Therapeutics Inc.: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc.: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Evopoint Biosciences Co.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|ICPD: Ownership Interest|ICPD Biosciences, LLC.: Ownership Interest|ICPD Holdings: Ownership Interest|ICPD Technologies: Ownership Interest|Insmed Inc.: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Menarini Ricerche S.p.A.: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novartis Pharmaceuticals Corp.: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|PureTech Health: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|TauRx Therapeutics: Grant/Research Support|Tetraphase Pharmaceuticals: Grant/Research Support|tranScrip Partners: Grant/Research Support|Utility Therapeutics: Grant/Research Support|Valanbio Therapeutics, Inc.: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support Ruben Tommasi, PhD, Entasis Therapeutics: Employee John O'Donnell, B.S, Entasis Therapeutics: Employee


Measles-Mumps-Rubella (MMR) is an effective live-virus vaccine against measles virus (MeV). However, use of MMR is limited by its inability to boost MeV immunity, lack of immunogenicity in infants, and contraindication in pregnant and immunocompromised persons.We evaluated a novel recombinant dimeric MeV hemagglutinin protein vaccine (rMeV) in a rhesus macaque model. Sixteen macaques were primed at day 0 and boosted at day 42 by experimental group: 1) MMR x2; 2) rMeV x2; 3) MMR prime/rMeV boost; 4) control; n=4. Macaques were challenged intratracheally with Bilthoven strain wild type MeV 8 months later. Blood, bone marrow (BM), and lymph node (LN) samples were collected over 3–28 days after challenge. Replication-competent MeV was measured in peripheral blood mononuclear cells (PBMC), BM cells, and LN cells by infectious assay; MeV RNA in PBMC and BM cells was determined by quantitative reverse transcriptase polymerase chain reaction. Plasma was evaluated for MeV-specific IgG and plaque reduction neutralization titer (PRNT).Six months after vaccination, mean PRNT was 2,432 in rMeV x2 (standard deviation (SD) 3,840), 3,584 in MMR-prime/rMeV boost  and 5,120 in MMR x2 groups . Upon infectious challenge, macaques who received any MeV-containing vaccine developed no clinical signs of measles and had no detectable infectious virus in PBMC, BM cells, or LN cells. All unvaccinated macaques had virus in PBMC that peaked at day 7  and resolved by day 14 post challenge, and one macaque developed an extensive rash. Macaques who received any MeV-containing vaccine had no detectable MeV RNA in PBMC or BM cells, whereas all unvaccinated macaques had detectable MeV RNA that peaked at day 7  in PBMC. In all experimental groups, MeV-specific IgG titers increased after MeV challenge.Macaques who received rMeV and/or MMR were protected from rash, viremia, and detection of MeV RNA in PBMC and BM cells, unlike unvaccinated macaques. These data suggest that rMeV vaccine generates protective immune responses against measles and may be a novel candidate for future measles vaccine strategies. Study of cellular responses after rMeV vaccination and MeV challenge is warranted.Jessica Rubens, MD, Mevox: Grant/Research Support Guillaume Stewart-Jones, PhD, Moderna: Inventor of SARS-CoV-2 vaccine sequences|Moderna: Stocks/Bonds Michael Watson, MD, MEVOX Ltd: Board Member|MEVOX Ltd: Ownership Interest|MEVOX Ltd: Stocks/Bonds Barney S. Graham, MD, PhD, BSG: BSG is an inventor on patents for the stabilization of the RSV F protein .|National Institutes of Health: Inventor on patents for RSV vaccines|National Institutes of Health: inventor on patents for measles and other paramyxovirus vaccines Diane Griffin, MD PhD, Gilead: Grant/Research Support|GlaxoSmithKline: Advisor/Consultant|GreenLight Biosciences: Advisor/Consultant|Merck: Advisor/Consultant|MeVox: Grant/Research Support|Takeda Pharmaceuticals: Advisor/Consultant.


Cryptococcal meningitis (CM) is a fungal disease with significant global morbidity and mortality. There are multiple new therapies being developed to improve the current regimens involving amphotericin B, flucytosine, and fluconazole. ATI-2307 is a novel arylamidine which inhibits mitochondrial function in yeasts. We tested ATI-2307 in a rabbit model of CM and evaluated its efficacy, pharmacokinetics, and pharmacodynamics (PK-PD).Immune suppressed rabbits were infected with Cryptococcus neoformans. Starting two days after the infection, they were treated with ATI-2307 , amphotericin B (1 mg/kg), fluconazole (80 mg/kg), a combination of ATI-2307 (1 mg/kg) and fluconazole (80 mg/kg), or they were untreated. ATI-2307 was given daily subcutaneously. Fungal burden and drug levels were quantified in the CSF during the infection and in the brain tissue at study termination, day 4, 10, or 14 post infection. Drug pharmacokinetics in the blood were examined on day 8 post infection. Drug pharmacokinetics in the CSF and brain tissue were examined at day 4 post infection.Daily dosing with ATI-2307 reduced the yeast burden in both the cerebrospinal fluid (CSF) and brain tissue compared to controls. Furthermore, when combined with fluconazole, ATI-2307 reduced the CSF fungal burden below the limit of detection. In fact, we observed a large reduction in fungal burden relative to untreated controls with only three doses, which was sustained for 1 week after the cessation of dosing. The kinetics of ATI-2307 indicated that the drug has a long gamma phase in both blood and CSF. In addition, our analysis of the drug levels in the brain tissue indicated that it dramatically accumulated in the meninges, which may then serve as a site of sustained release.Efficacy of ATI-2307 on CSF Fungal Burden and Distribution of ATI-2307 in Brain TissueATI-2307 was dosed daily starting at day 2 post infection through the study endpoint, day 10 or 14 post infection, with the exception of the 2 mg/kg, 3 dose group, which only received doses on days 2, 3, and 4 post infection.Taken together, these data provide evidence for ATI-2307 as a promising therapy for CM and it may require fewer doses than existing treatments and provide additive anticryptococcal activity with azole treatment.Charles D. Giamberardino, Jr., MR, Affimed NV: Stocks/Bonds|Appili Therapeutics: Grant/Research Support|Interventional Analgesix Inc: Grant/Research Support|Minnetronix: Grant/Research Support|Pfizer: Grant/Research Support|Quoin Pharmaceuticals: Stocks/Bonds|Sfunga: Grant/Research Support Jennifer L. Tenor, PhD, Appili: Grant/Research Support|Pfizer: Grant/Research Support Dena Toffaletti, PhD, Appili Therapeutics: Grant/Research Support|Pfizzer: Grant/Research Support Don Cilla, Pharm.D., M.B.A., Appili Therapeutics: Employee|Appili Therapeutics: Stocks/Bonds William Hope, OBE , Antabio: Grant/Research Support|Appili Therapeutics: Advisor/Consultant|BioVersys: Grant/Research Support|Bugworks: Grant/Research Support|Centauri: Advisor/Consultant|F2G: Advisor/Consultant|F2G: Grant/Research Support|NAEJA-RGM Pharmaceuticals Inc: Advisor/Consultant|NAEJA-RGM Pharmaceuticals Inc: Grant/Research Support|National Institute of Health Research (NIHR).: Co-lead for Infectious Diseases|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Phico Therapeutics: Grant/Research Support|Specialist Advisory Committee for GARDP: Advisor/Consultant|Spero Therapeutics: Advisor/Consultant|Spero Therapeutics: Grant/Research Support|The Global Antibiotic Research and Development Partnership (GARDP): Grant/Research Support|VenatoRx: Advisor/Consultant John R. Perfect, MD, Appili Therapeutics: Advisor/Consultant|Appili Therapeutics: Grant/Research Support|Astellas: Advisor/Consultant|Astellas: Grant/Research Support|Matinas: Advisor/Consultant|Merck: Advisor/Consultant|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Scynexis: Advisor/Consultant.


CRE isolates are considered a threat to human health. Until recently, the treatment options for CRE were limited. New BL/BLIs, such as ceftazidime-avibactam (CAZ-AVI), meropenem-vaborbactam (MVB), and imipenem-relebactam (IMI-REL), are active against most of these isolates, but these agents display some variation in activity. In this study, we evaluated the activity of these new BL/BLIs and comparator agents against CRE isolates collected in US hospitals.A total of 27,834 Enterobacterales isolates were collected in 74 US hospitals and susceptibility tested by reference broth microdilution methods. CLSI breakpoints were applied. CRE isolates resistant to imipenem or meropenem were submitted to whole genome sequencing and data analysis for the detection of β-lactamases.p=0.06). This increase was noted in isolates from bloodstream infections and among patients hospitalized with pneumonia; a slight decrease was observed among urinary tract infections. Among the CREs, an increase in E. cloacae, K. aerogenes, and less common Enterobacterales species was observed. CRE isolates included 8 species in 2019/2020 and 12 species in 2021. Most CRE isolates produced KPC enzymes, mainly KPC-2 and KPC-3, but a decline was noted over time, from 73.8% in 2019 to 67. 5% in 2020 and 54.1% in 2021. Conversely, MBLs increased from 3.8% in 2019 to 18.4% in 2021. MBLs were mainly NDM-1/-5, but also IMP-27 and IMP-4. OXA-48-like enzymes without NDM were detected among 8 isolates. Overall, CAZ-AVI inhibited 86.6% of CRE isolates. When comparing the activity of 3 new BL/BLIs tested against 2021 isolates, CAZ-AVI was active against 78.6% of the CRE isolates whereas MVB inhibited 76.5% and IMI-REL inhibited 73.3%.CRE comprised 0.9% (261) of the isolates. An increase in CRE prevalence was noted in 2021 (1.1%) compared to 2019 (0.8%) and 2020 (0.9%; An increase in CREs driven by an increase in MBL-producing isolates was noted in 2021. This increase is worrisome since there are no effective therapeutic options against MBL producers. CAZ-AVI was the most active agent against CREs, but the increase in MBLs should be closely monitored. New therapies against these isolates are urgently needed.Mariana Castanheira, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Timothy Doyle, MS, AbbVie: Grant/Research Support Valerie Kantro, BA, AbbVie: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Shionogi: Grant/Research Support Rodrigo E. Mendes, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Nabriva Therapeutics: Grant/Research Support|Office for Assistant Secretary of Defense for Health Affairs: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support|Spero Therapeutics: Grant/Research Support Helio S. Sader, MD, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|Melinta: Grant/Research Support|Nabriva Therapeutics: Grant/Research Support|Pfizer: Grant/Research Support.


Enterococcus is one of the major causes of nosocomial infections many with vancomycin resistance. About 50,000 infections are reported per year due to vancomycin-resistant Enterococci. Understanding the genotypic mutations can help recognize the potential burden for antibiotic resistance that exists in a population. In this study, using whole genome sequencing (WGS) we aim to analyze the prevalence of genetic resistance markers for commonly used antibiotics for Enterococcal treatment.E. faecium and 29 isolates of E. faecalis. The isolates were obtained from two different Detroit area hospitals from 2017-2019. The data from WGS was analyzed using EPISEQ CSTM  bioinformatic database to obtain specific resistance genes which would correspond to commonly used antibiotics for treatment of Enterococcal infections.Whole genome sequencing was performed using the NextSeq  on 60 isolates of Enterococcus faecium and Enterococcus faecalis investigated, we identified a total of 33 unique resistance genes across 18 classes of antibiotics (Table 1). We detected genetic mutations efmA, pbp5, tet(L), liar, liaS unique to E. faecium and only emeA unique to E. faecalis. E. faecium and E. faecalis share 14 similar resistance genes. E. faecium and E. faecalis had 12 and 7 unique resistance genes, respectively but are of same drug classes. The most common antibiotic classes include aminoglycosides, tetracyclines, quinolones, beta-lactams, glycopeptides, macrolides, and pyrimidine analogs.Among the 89 Enterococcus faecium had a greater number of resistance genes with glycopeptide, aminoglycoside, and beta lactam resistance when compared to Enterococcus faecalis. Whereas Enterococcus faecalis had more resistance genes associated with macrolides, tetracyclines, pyrimidine analogs, and Bactrim. In general, both appear to have many genes that encode for resistance to major classes of antibiotics which are used for treatment of Enterococcal infections. Further comparison with phenotypic susceptibility testing data would help better understand the practical implications of our resistance gene testing.Piyali Chatterjee, PhD, AHRQ Grant # 1R03HS027667-01: Grant/Research Support|AHRQ Grant # 1R03HS027667-01: Central Texas Veterans Health Care System Keith S. Kaye, MD, MPH, Allecra: Advisor/Consultant|GlaxoSmithKline plc.: Receiving symposia honoraria|GlaxoSmithKline plc.: GlaxoSmithKline plc.-sponsored study 212502|Merck: Advisor/Consultant|qpex: Advisor/Consultant|Shionogi: Grant/Research Support|Spero: Advisor/Consultant Chetan Jinadatha, MD, MPH, AHRQ R01 Grant-5R01HS025598: Grant/Research Support|EOS Surfaces: Copper Coupons and materials for testing.


It remains unclear if there is an association between COVID-19 and cryptococcosis. The purpose of this study was to compare demographic characteristics and outcomes of cryptococcosis between patients with COVID-19 to non-COVID-19 controls.Patients 18 years and older with cryptococcosis were identified from TriNetX, a global federated research network, and separated into two cohorts based on a diagnosis of COVID-19 within 3 months prior to the index diagnosis of cryptococcosis. The primary outcome was the percent mortality in each group. The secondary outcomes included the proportion of patients in each group who had underlying comorbidities, received immunosuppressive medications, or required hospitalization or ICU admission. Propensity score matching was performed to control for differences between groups based on demographics and comorbidities. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for outcomes, with p < 0.05 as the cut off for statistical significance.A total of 6252 patients with cryptococcosis were included, of which 4.5% (n=283) had COVID-19 prior to diagnosis of cryptococcosis. Mortality was similar between patients with and without COVID-19 . Patients with cryptococcosis and previous COVID-19 were older  and more likely to be non-Hispanic . More patients with COVID-19 had a history of transplant , malignancy , and diabetes , but not HIV . Prednisone and dexamethasone use were higher among patients with previous COVID-19 . Hospitalization rates were similar , but more patients with COVID-19 required ICU admission . In propensity score-matched analysis, patients with COVID-19 remained at higher odds of ICU admission , but lower odds of hospitalization .Patients with COVID-19 who developed cryptococcosis had higher rates of comorbidities, corticosteroid use, and ICU admission but did not experience higher mortality compared to non-COVID-19 controls.George R. Thompson, III, MD, Amplyx: Advisor/Consultant|Amplyx: Grant/Research Support|Astellas: Advisor/Consultant|Astellas: Grant/Research Support|Cidara: Advisor/Consultant|Cidara: Grant/Research Support|F2G: Advisor/Consultant|F2G: Grant/Research Support|Merck: Grant/Research Support|Pfizer: DSMB|Scynexis: Advisor/Consultant|Scynexis: Grant/Research Support.


Two years into the pandemic, clinicians do not have access to a standardized measurement of SARS-CoV-2 viral load (VL) that allows for VL comparison across clinical specimens and different assays. Reliable VL measurement in diverse respiratory specimens, over time, and in response to treatments such as remdesivir (RDV), could better inform treatment and prevention.To investigate the use of a standardized VL assay in respiratory specimens, we enrolled patients hospitalized with COVID-19 in Providence, RI, with/without RDV exposure; collected serial samples from 4 compartments  in 3 visits during the 1st week of hospitalization; and characterized SARS-CoV-2 VL using a ChromaCode HDPCR™ quantitative research use only assay, calibrated to the first World Health Organization (WHO) International Standard (IS). Linear mixed effects models and associated regression coefficients were used to analyze inter-compartmental VL differences at enrollment, over time, and with/without RDV.10IU/mL) differed by compartment at visit 1  and significantly decreased over time in all compartments . Log VL change over time was not significantly different between compartments or between people treated/not treated with RDV.Of 35 participants , all had visit 1 samples ; 80% visit 2 samples ; and 37% visit 3 samples . Overall, 38 NP, 67 NA, 57 OP, and 67 SA samples were collected. Mean log VLs (LogWe successfully measured respiratory intercompartmental SARS-CoV-2 VL differences among hospitalized patients using a standardized assay calibrated to the WHO IS. Dissemination of standardized VL measurement methods will allow accurate VL comparisons across assay types quantified in IU/mL and improve assessment of the impact of COVID-19 treatments. Inter-compartmental VL differences at baseline may indicate sampling variability or different viral burden. RDV did not appear to accelerate viral decay.Curt Beckwith, MD, Gilead Sciences, Inc: Grant/Research Support Jon Steingrimsson, PhD, Gilead: Grant/Research Support Angela Caliendo, MD, PhD, ChromaCode: Advisor/Consultant|Danaher/Cepheid: Advisor/Consultant|First Light: Advisor/Consultant|Hologic: Grant/Research Support|ID Connect: Advisor/Consultant|Quidel: Advisor/Consultant|Visby: Advisor/Consultant Rami Kantor, MD, Gilead Sciences: Grant/Research Support.


Articles:Interactive structural color displays of nano-architectonic 1-dimensional block copolymer photonic crystalsTae Hyun Park, Seunggun Yu, Jeongok Park and Cheolmin Parkhttps://doi.org/10.1080/14686996.2022.2156256Deep-learning-based inverse design of three-dimensional architected cellular materials with the target porosity and stiffness using voxelized VoronoilatticesXiaoyang Zheng, Ta-Te Chen, Xiaoyu Jiang, Masanobu Naito and Ikumu Watanabehttps://doi.org/10.1080/14686996.2022.2157682Recent advances in neuromorphic transistors for artificial perception ApplicationsWei Sheng Wang and Li Qiang Zhuhttps://doi.org/10.1080/14686996.2022.2152290Journal: Science and Technology of Advanced MaterialsBibliometrics: Volume 24, Number 1When first published online, the three articles above were published with incorrect pagination from page 2 onwards. These have now been corrected accordingly, with the article ID on page one remaining unchanged, and the following pages beginning from page 2.


Letermovir (LTV) for CMV prophylaxis in allogeneic hematopoietic cell transplant (HCT) recipients has decreased utilization of broad-spectrum antivirals for CMV, which may result in more frequent reactivation of herpesviruses not targeted by LTV. We hypothesized that the cumulative incidence of HHV-6 and EBV reactivation, and associated diseases, within 100 days after HCT would increase following the introduction of LTV.We conducted a retrospective study of CMV-seropositive adults who received an allogeneic HCT at our center prior to (5/2015 – 9/2018) and after (10/2018 – 12/2021) routine use of LTV. We reviewed medical records for antiviral use, viral testing, and virus-associated end-organ disease within days 0-100 after HCT. Testing was performed at the discretion of healthcare providers or according to treatment protocols. We computed cumulative incidence estimates treating death and subsequent HCT as competing risks.Figure 1). Two patients in each cohort (0.5%) developed proven or probable HHV-6 encephalitis. Median peak plasma HHV-6 viral load was nearly 1 log10 higher in the LTV cohort . The incidence of tests for and detection of EBV was higher in the LTV cohort, but the proportion of patients with ≥ 1 positive test among tested patients was similar (14% pre-LTV vs 20% post-LTV); of note, EBV testing in both cohorts was mainly protocol driven . There were no cases of PTLD by day 100 in either cohort.We identified 403 patients prior to and 378 patients after routine use of LTV. Characteristics were similar between cohorts except for more frequent use of post-transplant cyclophosphamide for GVHD prophylaxis in the LTV cohort. Broad-spectrum antiviral use, as estimated by available data, was 68% pre-LTV versus 23% post-LTV. The incidence of tests for and detection of HHV-6 were similar in both cohorts (Despite a 66% decrease in broad-spectrum antiviral use after the introduction of LTV prophylaxis in CMV-seropositive allogeneic HCT recipients, there was no evidence for increased HHV-6 or EBV reactivation and associated end-organ diseases. Whether the higher peak HHV-6 viral load in the LTV cohort has clinical implications requires further study.Danielle M. Zerr, MD MPH, AlloVir: Advisor/Consultant Michael J. Boeckh, MD PhD, Allovir: Advisor/Consultant|Amazon: Grant/Research Support|Ansun Biopharma: Grant/Research Support|EvrysBio: Advisor/Consultant|Gates Ventures: Grant/Research Support|Gilead Sciences: Advisor/Consultant|Gilead Sciences: Grant/Research Support|GlaxoSmithKline: Advisor/Consultant|GlaxoSmithKline: Grant/Research Support|Helocyte: Advisor/Consultant|Janssen: Advisor/Consultant|Janssen: Grant/Research Support|Kyorin Pharmaceuticals: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Moderna: Advisor/Consultant|Moderna: Grant/Research Support|Regeneron: Grant/Research Support|ReViral: Advisor/Consultant|Symbio: Advisor/Consultant|Takeda: Grant/Research Support|Vir Biotechnology: Advisor/Consultant|Vir Biotechnology: Grant/Research Support Joshua A. Hill, MD, Allovir: Advisor/Consultant|Allovir: Grant/Research Support|Covance/CSL: Advisor/Consultant|CRISPR: Advisor/Consultant|Deverra: Grant/Research Support|Gilead: Grant/Research Support|Karius: Advisor/Consultant|Karius: Grant/Research Support|Merck: Grant/Research Support|Octapharma: Advisor/Consultant|OptumHealth: Advisor/Consultant|Oxford Immunotec: Grant/Research Support|Pfizer: Advisor/Consultant|Symbio: Advisor/Consultant|Takeda: Advisor/Consultant.


Correction: BMC Health Services Research (2022) 22:1257https://doi.org/10.1186/s12913-022-08625-8Following publication of the original article , the autThe incorrect author names are: Buffel Veerle, Danhieux Katrien, Remmen Roy, Van Olmen Josefien and Wouters EdwinThe correct author names are: Veerle Buffel, Katrien Danhieux, Roy Remmen, Josefien Van Olmen and Edwin WoutersThe author group has been updated above and the original article  has been


Clostridioides difficile infection (CDI) among adults < 65 years of age.Limited data are available on healthcare costs associated with This retrospective cohort study used Optum’s de-identified Clinformatics® Data Mart to identify first CDI episodes from 2016–2019 among individuals 18–64 years of age insured under commercial plans. CDI was defined by ICD9/ICD10 diagnosis codes or a combination of CDI diagnosis/testing with antibiotic treatment. Healthcare costs were evaluated among CDI+ cases and 1:1 propensity score-matched CDI− controls. Both CDI+ cases and controls had continuous database enrollment for ≥12 months prior; follow-up continued through the earliest of death, disenrollment or 12 months post-index. Costs were analyzed by age group, acquisition type, and hospitalization status within 2 months of the CDI index date.Figure 1A). Mean attributable costs were higher for hospitalized healthcare-associated  and hospitalized community-associated  cases than non-hospitalized healthcare- or community-associated cases . The mean attributable out-of-pocket (OOP) cost in the 50–64-year age group was $573 and was higher for community-associated vs healthcare-associated cases . Overall CDI-attributable costs in the 18–49-year age group trended similarly but were mostly lower for total healthcare costs  and slightly higher for OOP healthcare costs .We identified 13,820 CDI+ cases and 4,027,386 potential controls; 12,999 cases  were matched to a control. In the 50–64-year matched groups, mean total healthcare costs at 2 months post-index were $18,453 (CDI+) and $6819 (CDI−); $11,634 in excess costs were attributable to CDI (CDI-attributable healthcare costs among US individuals 18–64 years of age are substantial, particularly for those hospitalized for CDI. Effective prevention in younger adults may significantly reduce healthcare resource utilization and costs to both the healthcare system and patients.Funded by Pfizer Inc.Holly Yu, MSPH, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Tamuno Alfred, PhD, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Jingying Zhou, MA, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Jennifer Judy, MS, PhD, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Margaret A A. Olsen, PhD, MPH, Pfizer Inc: Advisor/Consultant|Pfizer Inc: Grant/Research Support.


J Pediatr 2022;241:203-11), we demonstrated that in-person training in a structured communication strategy called AIMS  resulted in behaviors of interest during live encounters with standardized patients (SPs) portraying vaccine-hesitant parents. We investigated whether similar effects would be seen if training and SP encounters occurred in a virtual environment.There are no accepted best practices for counseling vaccine-hesitant parents, and training in this area is not required in residency. In a prior study , developed and characterized in the initial study but modified based on factor analysis to improve reliability and validity. Subject confidence and SP evaluations of the encounter were assessed pre- and post-training. Investigators, subjects, SPs, and video raters were blinded to treatment allocation.Fifty-three subjects completed the protocol and 47 had complete video files. Subject confidence improved in both groups (Panel A). No differences in SP evaluations were detected between groups (B). Preliminary analysis demonstrated that AIMS behaviors were more commonly detected among AIMS-trained subjects than control, as evidenced by an increase in VHCA score (C).Communication training and assessment using SPs were both successfully transitioned to a virtual environment; this opens the possibility of efficient training and assessment of residents who are not located on site. Training increased confidence non-specifically. Encounters with SPs can serve as a model to detect learned vaccine-specific communication behaviors among resident providers, but post-encounter assessments by SPs remained insensitive to differences in those behaviors despite modification of the case materials.Shanna M. Barton, MD, M.Sc., Sanofi Pasteur: Grant/Research Support Aaron W. Calhoun, MD, FSSH, Sanofi-Pasteur: Grant/Research Support|Society for Simulation in Healthcare: Board Member|Society for Simulation in Healthcare: Honoraria Victoria A. Statler, M.D., M.Sc., Astellas: University Research Support|Gilead: University Research Support|Pfizer: Advisor/Consultant|Sanofi: University Research Support|Seqirus: Advisor/Consultant Gary S. Marshall, MD, GlaxoSmithKline: Advisor/Consultant|GlaxoSmithKline: Grant/Research Support|GlaxoSmithKline: Honoraria|Merck: Advisor/Consultant|Merck: Grant/Research Support|Merck: Honoraria|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Pfizer: Honoraria|Sanofi: Advisor/Consultant|Sanofi: Grant/Research Support|Sanofi: Honoraria|Seqirus: Advisor/Consultant|Seqirus: Grant/Research Support|Seqirus: Honoraria.


Inability to define microbial etiology of lower respiratory tract infection (LRTI) leads to unnecessary antibiotic use. Though multiplex PCR improves viral detection, bacterial LRTI diagnosis remains problematic. We evaluated the clinical utility of BioFire ® FilmArray ® Pneumonia (PN) Panel which detects 8 viruses, 3 atypical and 15 pathogenic bacteria by semi-quantitative PCR to inform bacterial diagnosis.As part of a study to distinguish bacterial from non-bacterial LRTI in hospitalized adults, clinical, laboratory, and X-ray data were collected. Adequate sputa  processed by Gram stain and culture were tested with FilmArray® PN. Microbial LRTI etiology  was adjudicated by a four physician panel using all clinical data except bacterial PCR results. Bacterial PCR was compared to Gram stain and culture and clinical adjudication.From 737 illnesses evaluated, 423 sputa were collected and 201 deemed adequate and were tested with FilmArray® PN. Most common discharge diagnoses were pneumonia (24%), AECOPD (21%), viral illness (13%) and asthma exacerbations (9%). FilmArray® PN detected 155 typical bacteria, 9 atypical and 101 viruses. Most bacterial detections were monomicrobial (58%) often with concomitant viruses (43%). Compared to Gram stain and culture, FilmArray® PN detected more bacterial pathogens and was less affected by antibiotics.  Cases were adjudicated as viral Alone (37), bacterial (93) and indeterminate (71). Bacteria were detected by PCR in 41% of viral and 96% of bacterial cases, p=0.0001 and 76% of indeterminate cases. In cases with no bacteria detected by PCR, only 4 (9%) were adjudicated as bacterial; all deemed caused by anaerobic bacteria which are not included in the PCR panel. Comparing bacterial vs. non-bacterial , FilmArray® PN bacterial PCR had 96% sensitivity, 36% specificity, 56% positive predictive value and 91% negative predictive value. Finally, sputum PCR detected 4 mycoplasma and 56 viral infections missed by standard of care testing.Multiplex PCR testing of sputa for bacteria is useful to rule out bacterial infection with added value to detect viruses and atypical bacteria.Ann R. Falsey, MD, BioFire Diagnostics: Grant/Research Support|Janssen: Grant/Research Support|Merck, Sharp and Dohme: Grant/Research Support|Novavax: Advisor/Consultant|Pfizer: Grant/Research Support Angela R. Branche, MD, Cyanvac: Grant/Research Support|GSK: Advisor/Consultant|Janssen: Advisor/Consultant|Merck: Expert Testimony|Pfizer: Grant/Research Support Edward E. Walsh, MD, Janssen: Advisor/Consultant|Janssen: Grant/Research Support|Janssen: Honoraria|Merck: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support.


Scientific Reports 10.1038/s41598-022-10254-4, published online 13 April 2022Correction to: The original version of this Article contained an error in the legend of Figure 1.http://www.esri.com).”“Study area along with the well and infiltration sites on the geomorphic map in a part of the Ganga basin, Northern India .”“Study area along with the well and infiltration sites on the geomorphic map in a part of the Ganga basin, Northern India .”“Monthly groundwater level at 50 observation wells of a dense monitoring network from February 2012 to March 2014 were accessed and utilized for the analysis. The monthly rainfall data were also collected from January 2010 to December 2019 . Report on pilot project on aquifer mapping in Maner-Khagaul area, Patna District Bihar (Watershed -GNDK013), p. 260 (2015).The correct reference is listed below:http://cgwb.gov.in/AQM/Pilot/Patna%20District,%20Bihar-Final.pdfCentral Ground Water Board (CGWB). Report on pilot project on aquifer mapping in Maner-Khagaul area, Patna District Bihar (Watershed -GNDK013), p. 260 (2015). Furthermore, the Acknowledgements section was incomplete.“Prof. V.M. Tiwari, Director of CSIR-National Geophysical Research Institute, Hyderabad, has encouraged and permitted to publish this article (Ref. No: NGRI/Lib/2021/Pub-18). The DST-NGP (GoI), New Delhi , January 21, 2021) has funded this research work. Authors are thankful to them.”now reads:“Prof. V.M. Tiwari, Director of CSIR-National Geophysical Research Institute, Hyderabad, has encouraged and permitted to publish this article (Ref. No: NGRI/Lib/2021/Pub-18). The DST-NGP (GoI), New Delhi , January 21, 2021) has funded this research work. Central Ground Water Board (CGWB), Ministry of Jal Shakti, Department of Water Resources, River Development and Ganga Rejuvenation (GoI) has generated the hydrogeological data. Authors are thankful to them."Lastly, the Data availability section was incomplete.“The data sets both generated and analysed during the current study are available from the corresponding author on reasonable request.”now reads:http://cgwb.gov.in/AQM/Pilot/Patna%20District,%20Bihar-Final.pdf and the analyzed information during the current study are available from the corresponding author on reasonable request”“The data source: The original Article has been corrected.


Aspergillus spp (including azole-resistant strains), rare, resistant moulds  and dimorphic moulds.Olorofim is a novel antifungal agent active against Serial images of Lomentospora prolificans infection following breast enhancement surgery: progression of healing pre- and post-olorofim therapy.Post-surgical bone/ soft tissue Lomentospora prolificans infection of the chest wall in a healthy woman was uncontrolled with available agents (D -9 visible mould in wound base). At D42/84 overall response on olorofim monotherapy was stable; wound closure with complete resolution of IFI was achieved at D322 .1 received oral olorofim (150mg BID x1d loading dose then 90mg BID). Outcomes in the first 100 patients are compared with historical controls (HCs) as well as with expected outcomes in patients with baseline highly active, uncontrolled IFI (HAU-IFI).Patients with limited/no treatment options for proven invasive fungal infection (IFI) or probable pulmonary invasive aspergillosis (IA) using EORTC-MSGERC criteria2  was 47%/42% in IA , 53%/53% , 55%/36% , and 50%/50% . Stable response at D42/D84 predicted extended therapy responses, especially in HAU-IFI of brain and bone . For Coccidioides (n=11) OR was limited to stable due to very slow clearance of fungal serology but clinical response was rapid. Symptoms resolved completely in 18% (2/11) by D84 vs 3% (1/29) by D1523 in comparable HCs with poorly controlled extrapulmonary Coccidioides infection; similar trends were seen for other response measures.All-cause mortality in IA at month 3  was 17/53  for olorofim vs. 40/46  in HCs given either no therapy or azole monotherapy for azole-resistant IA. Successful EORTC-MSGERC overall response3, considering stable in overall success if often appropriate when assessing responses in non-IA mould IFI.Olorofim is a novel oral antifungal with activity against a wide range of mould infections which are difficult to treat. Compared with relevant HCs or expected outcomes for HAU-IFI, olorofim has a positive benefit-risk profile in a well-defined population of patients with limited/no treatment options. As noted previouslyReferences:1. Donnelly CID 2020; 71:1367–762. Segal CID 2008; 47:674–833. Perfect Mycoses 2018: 61:420Johan A. Maertens, MD PhD, F2G Ltd: Advisor/Consultant|Gilead Sciences Ltd: Advisor/Consultant|Mundipharma: Advisor/Consultant|Pfizer Inc: Advisor/Consultant Paul E. Verweij, PhD, Gilead: Grant/Research Support Emma L. Harvey, MBBS, F2G Ltd: Stocks/Bonds Aaron Dane, MSc, Amplyx: Advisor/Consultant|AN2 therapeutics: Advisor/Consultant|Artizan: Advisor/Consultant|Cidara: Advisor/Consultant|ContraFect: Advisor/Consultant|Correvio: Advisor/Consultant|Davolterra: Advisor/Consultant|Destiny Pharma: Advisor/Consultant|Entasis: Advisor/Consultant|F2G Limited: Advisor/Consultant|GSK: Advisor/Consultant|Humanigen: Advisor/Consultant|Kymab: Advisor/Consultant|Modis: Advisor/Consultant|Orca: Advisor/Consultant|Pfizer: Advisor/Consultant|Phico: Advisor/Consultant|Pled Pharma: Advisor/Consultant|Rare Thyroid: Advisor/Consultant|Roche: Advisor/Consultant|Scynexis: Advisor/Consultant|Sinovent: Advisor/Consultant|Spero Therapeutics: Advisor/Consultant|Transcrip: Advisor/Consultant|Venatorx: Advisor/Consultant Daniela Zinzi, Infectious Diseases Specialist, F2G: F2G employee|F2G: Stocks/Bonds John H. Rex, MD, Advent Life Sciences: Operating Partner|Advent Life Sciences: Ownership Interest|AMR Action Fund: Advisor/Consultant|AstraZeneca: Stocks/Bonds|Basilea Pharmaceutica: Advisor/Consultant|Bugworks Research, Inc.: Advisor/Consultant|F2G, Limited: Employee|F2G, Limited: Stocks/Bonds|Forge Therapeutics: Advisor/Consultant|GlaxoSmithKline: Advisor/Consultant|Pfizer Pharmaceuticals: Honoraria|Sumitovant: Advisor/Consultant Sharon C. Chen, PhD MBBS, F2G PTy Ltd: Grant/Research Support|MSD Australia: Grant/Research Support.


Letermovir (LTV) has reduced non-relapse mortality (NRM) in allogeneic hematopoietic cell transplant  recipients by reducing the rate of clinically significant cytomegalovirus infections (CS-CMVi). The impact of LTV prophylaxis (PP) on other infections is unclear. We investigated the effects of LTV on human herpes virus 6 (HHV6) DNAemia in HCT recipients with or without CS-CMVi and studied the interaction of HHV6 DNAemia with CS-CMVi and its impact on NRM.We performed a single center, retrospective cohort study from March 2016 to December 2018 of consecutive allo-HCT recipients who are CMV recipient seropositive (R+) with or without LTV prophylaxis. Baseline characteristics and infectious complications data were collected. Outcomes of interest was NRM at 100 days, 24 weeks and 48 weeks post allo-HCT. Univariate analysis was performed to identify risk factors for HHV6 reactivation within the first year including CS-CMVi and risk factors for NRM at 48 weeks post transplant. A logistic regression was performed to identify independent risk factors for HHV6 DNAemia and NRM at 48 weeks. Patients with relapse were excluded from NRM analysis.A total of 539 allo-HCT recipients were included in our analysis; 124 (23%) with and 415 (77%) without LTV PP. HHV6 DNAemia was identified in 111 (21%) allo-HCT recipients within the first year of transplant, where CS-CMVi occurred in 241 (45%) (table 1). Risk factors for HHV6 DNAemia included African American race, underlying ALL, Haploidentical or cord HCT, marrow or cord source of stem cells, use of Post-cyclophosphamide, and CS-CMVi. On multivariate analysis, CS-CMVi was the only independent predictor of HHV6 reactivation (Adjusted OR: 1.69) (table 1). Independent predictors of NRM on logistic regression included CS-CMVi , and age > 40 years , and matched related donor allo-HCT  as a protective factor (table 2).HHV6 DNAemia is strongly associated with CS-CMVi, which is probably a reflection of poor T cell recovery post HCT such as Haploidentical or Cord blood HCT. Furthermore, CS-CMVi was associated with NRM whereas HHV6 DNAemia was not. Larger studies are needed to better elucidate this interaction.Gabriella Rondon, MD, Omeros: Advisor/Consultant Elizabeth Shpall, MD, Adaptimmune: Advisor/Consultant|Affimed: License agreement|Axio: Advisor/Consultant|Bayer Helathcare Pharmaceuticals: Honoraria|Fibroblasts and FibrioBiologics: Advisor/Consultant|Navan: Advisor/Consultant|NY Blood Center: Advisor/Consultant|Takeda: License agreement Ella Ariza-Heredia, MD, MERCK: Grant/Research Support Roy F. Chemaly, MD/MPH, Karius: Advisor/Consultant|Karius: Grant/Research Support.


Adult respiratory syncytial virus (RSV) vaccines are in late stages of development. A comprehensive synthesis of adult RSV burden is needed to inform public health decision-making.ie, serology or sputum).We performed a systematic review and meta-analysis of studies describing the incidence of medically-attended RSV (MA-RSV) among US adults. We also identified studies reporting nasopharyngeal (NP) or nasal swab RT-PCR results with paired serology (four-fold-rise) or sputum (RT-PCR) to calculate RSV detection ratios quantifying improved diagnostic yield after adding a second specimen type  hospitalizations , 133  emergency department (ED) admissions, and 1519  outpatient visits. Based on 6 studies, RSV detection was ∼1.5 times higher when adding paired serology or sputum. After adjustment for this increased yield, annual RSV-associated rates per 100,000 adults ≥65 years were 267 hospitalizations (UI: 228‒306) , 200 ED admissions (UI: 0‒478), and 2278 outpatient visits (UI: 1663‒2893). Persons < 65 years with chronic medical conditions were 1.2−28 times more likely to be hospitalized for RSV depending on risk condition.The true burden of RSV has been underestimated and is significant among older adults and individuals with chronic medical conditions. A highly effective adult RSV vaccine would have substantial public-health impact.John M. McLaughlin, PhD, Pfizer: Employee|Pfizer: Stocks/Bonds Farid L. Khan, MPH, Pfizer: Employee|Pfizer: Stocks/Bonds Elizabeth Begier, M.D., M.P.H., Pfizer: Employee|Pfizer: Stocks/Bonds David Swerdlow, MD, Pfizer: Advisor/Consultant|Pfizer: Stocks/Bonds Luis Jodar, PhD, Pfizer: Employee|Pfizer: Stocks/Bonds Ann R. Falsey, MD, BioFire Diagnostics: Grant/Research Support|Janssen: Grant/Research Support|Merck, Sharp and Dohme: Grant/Research Support|Novavax: Advisor/Consultant|Pfizer: Grant/Research Support.


Invasive fusariosis (IF) is an uncommon opportunistic mold infection primarily affecting patients (pts) with leukemia and allogeneic hematopoietic cell transplant (HSCT). Historically, IF had poor outcome when there is lack of recovery from immunosuppression. However, IF incidence and outcome in the in the era of new mold-active triazoles and leukemia regimens that incorporate molecularly targeted drugs is unknown.We retrospectively studied the incidence, risk factors, clinical features, and outcome of microbiologically documented IF (revised EORTC/MSG criteria) in pts with leukemia at MD Anderson Cancer Center in the last 12 years (June 2009-October 2021). The independent risk factors for 42-day (d) mortality from IF diagnosis were assessed by a binary multivariable logistic regression model. Annual incidence density (1998-2021) was estimated using Poisson regression analysis.Figure 1).Among 140 IF pts , 100 (71%) had pneumonia, 88 (63%) disseminated infection, and 32 (23%) sinusitis, with no apparent changes in relative frequency over the years. 124 pts (89%) had neutropenia (ANC < 500) at IF diagnosis, 118 (84%) had relapsed/refractory (R/R) leukemia, and 43 (31%) had prior HSCT. 19% (18/97 pts) of IF pts had positive serum galactomannan and 55% had coinfections. In the last 5 years of the study, 45/58 IF cases (78%) were breakthrough infections to mold active triazoles . 74 (53%) out of the 140 IF pts died by d42. Only 6 pts (9%) had neutrophil recovery at time of death compared to 47 (64%) who survived until day 42 (P < 0.001). Neutrophil recovery , SOFA score , and pneumonia  were independent predictors of 42-d mortality. Since 1998, the incidence density of IF continuously increased (P = 0.006) at an annual ratio of 1.05 , AbbVie: Advisor/Consultant|Astellas Pharma: Advisor/Consultant|Astellas Pharma: Grant/Research Support|Astellas Pharma: Honoraria|Cidara Therapeutics: Advisor/Consultant|Gilead Sciences: Advisor/Consultant|Gilead Sciences: Grant/Research Support|Gilead Sciences: Honoraria|Merck: Advisor/Consultant.


Studies show that past SARS-CoV-2 infection provides a protective immune response against subsequent COVID-19, but the degree of protection from prior infection has not been determined.History of previous SARS-COV-2 Infection and Current SARS-COV-2 Infection Status at Admission.*Adjusted for chronic respiratory disease and prior COVID-19 vaccinationFrom May 2021 through Feb 2022, adults (≥ 18 years of age) hospitalized at Emory University Hospital and Emory University Hospital Midtown with acute respiratory infection (ARI) symptoms, who were PCR tested for SARS-CoV-2 were enrolled. A prior history of SARS-CoV-2 infection was obtained from patient interview and medical record review. Previous infection was defined as a self-reported prior SARS-CoV-2 infection or previous evidence of a positive SARS-CoV-2 PCR test ≥ 90 days before ARI hospital admission. We performed a test negative design to evaluate the protection provided by prior SARS-CoV-2 infection against subsequent COVID-19-related hospitalization. Effectiveness was determined using logistic regression analysis adjusted for patient sociodemographic and clinical characteristics and COVID-19 vaccination status.Of 1152 adults hospitalized for ARI, 704/1152 (61%) were SARS-CoV-2 positive. 96/1152 (8%) had a prior SARS-CoV-2 infection before hospital admission. Patients with a previous history of SARS-CoV-2 infection were less likely to test positive for SARS-CoV-2 upon admission for ARI compared to those who did not have evidence of prior infection .Reinfections represented a small proportion (< 10%) of COVID-19-related hospitalizations. Prior SARS-CoV-2 infection provided meaningful protection against subsequent COVID-19-related hospitalization. The durability of this infection-induced immunity, variant-specific estimates, and the additive impact of vaccination are needed to further elucidate these findings.Laura A. Puzniak, PhD. MPH, Merck & Co., Inc.: Stocks/Bonds|Pfizer, Inc.: Stocks/Bonds Robin Hubler, MS, Pfizer Inc.: Employee|Pfizer Inc.: Stocks/Bonds Srinivas Valluri, PhD, Pfizer: Employee|Pfizer: Stocks/Bonds Benjamin Lopman, PhD, Epidemiological Research and Methods, LLC: Advisor/Consultant Satoshi Kamidani, MD, NIH: His institution (Emory University) receives funds from Pfizer for his work as a co-investigator on clinical trials of Pfizer COVID-19 vaccine.|Pfizer: His institution (Emory University) receives funds from Pfizer for his work as a co-investigator on clinical trials of Pfizer COVID-19 vaccine. Christina A. Rostad, MD, BioFire Inc, GSK, MedImmune, Micron, Merck, Novavax, PaxVax, Pfizer, Regeneron, Sanofi-Pasteur.: Grant/Research Support|Meissa Vaccines, Inc.: Co-inventor of RSV vaccine technology licensed to Meissa Vaccines, Inc.|NIH : Grant/Research Support John M. McLaughlin, PhD, Pfizer: Employee|Pfizer: Stocks/Bonds Evan J. Anderson, MD, GSK: Advisor/Consultant|GSK: Grant/Research Support|Janssen: Advisor/Consultant|Janssen: Grant/Research Support|Kentucky Bioprocessing, Inc: Data Safety Monitoring Board|MedImmune: Grant/Research Support|Medscape: Advisor/Consultant|Merck: Grant/Research Support|Micron: Grant/Research Support|NIH: Funding from NIH to conduct clinical trials of Moderna and Janssen COVID-19 vaccines|PaxVax: Grant/Research Support|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Regeneron: Grant/Research Support|Sanofi Pasteur: Advisor/Consultant|Sanofi Pasteur: Grant/Research Support|Sanofi Pasteur: Data Adjudication and Data Safety Monitoring Boards|WCG and ACI Clinical: Data Adjudication Board.