Review

. 2023 Oct 16;77(Suppl 4):S295-S304.

doi: 10.1093/cid/ciad565.

Priorities and Progress in Gram-positive Bacterial Infection Research by the Antibacterial Resistance Leadership Group: A Narrative Review

Sarah B Doernberg¹, Cesar A Arias^{2

3

4}, Deena R Altman^{5

6}, Ahmed Babiker^{7

8}, Helen W Boucher⁹, C Buddy Creech^{10

11}, Sara E Cosgrove¹², Scott R Evans¹³, Vance G Fowler¹⁴, Stephanie A Fritz¹⁵, Toshimitsu Hamasaki¹⁶, Brendan J Kelly¹⁷, Sixto M Leal¹⁸, Catherine Liu^{19

20}, Thomas P Lodise²¹, Loren G Miller^{22

23}, Jose M Munita^{24

25}, Barbara E Murray²⁶, Melinda M Pettigrew²⁷, Felicia Ruffin¹⁴, Marc H Scheetz²⁸, Bo Shopsin^{29

30}, Truc T Tran³, Nicholas A Turner¹⁴, Derek J Williams³¹, Smitha Zaharoff³², Thomas L Holland¹⁴; Antibacterial Resistance Leadership Group

Collaborators, Affiliations

Collaborators

Antibacterial Resistance Leadership Group:
Robin Patel, Heather King, Tori Kinamon, Weixiao Dai, Holly Geres, Nancie Deckard, Carl Schuler, Ivra Bunn, Shrabani Sharma, Cathy Wickward, Jason Waller, Holly Wilson, Maureen Mehigan, Varduhi Ghazaryan, Erica Raterman, Tamika Samuel, Marina Lee

Affiliations

¹ Division of Infectious Diseases, Department of Medicine, University of California, SanFrancisco, California, USA.
² Division of Infectious Diseases, Department of Medicine, Houston Methodist Hospital, Houston, Texas, USA.
³ Center for Infectious Diseases, Houston Methodist Research Institute, Houston, Texas, USA.
⁴ Department of Medicine, Weill-Cornell Medical College, New York, New York, USA.
⁵ Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
⁶ Department of Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, NewYork, New York, USA.
⁷ Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
⁸ Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
⁹ Tufts University School of Medicine, Medford, Massachusetts, USA.
¹⁰ Division of Pediatric Infectious Diseases, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
¹¹ Vanderbilt Vaccine Research Program, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
¹² Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
¹³ Department of Biostatistics, George Washington University, Washington, District of Columbia, USA.
¹⁴ Division of Infectious Diseases, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA.
¹⁵ Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St Louis, Missouri, USA.
¹⁶ Biostatistics Center, George Washington University, Rockville, Maryland, USA.
¹⁷ Division of Infectious Diseases, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
¹⁸ Department of Laboratory Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
¹⁹ Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA.
²⁰ Division of Allergy and Infectious Diseases, University of Washington, Seattle, Washington, USA.
²¹ Department of Pharmacy Practice, Albany College of Pharmacy and Health Sciences, Albany, New York, USA.
²² Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California, USA.
²³ Division of Infectious Diseases, Lundquist Institute at Harbor-UCLA Medical Center, Torrance, California, USA.
²⁴ Instituto de Ciencias e Innovación en Medicina, Facultad de Medicina Clinica Alemana, Universidad del Desarrollo, Santiago, Chile.
²⁵ Multidisciplinary Initiative for Collaborative Research on Bacterial Resistance, Santiago, Chile.
²⁶ Division of Infectious Diseases, Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA.
²⁷ Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, Connecticut, USA.
²⁸ Pharmacometrics Center of Excellence, College of Pharmacy, Midwestern University, Downers Grove, Illinois, USA.
²⁹ Division of Infectious Diseases, Department of Medicine, New York University Grossman School of Medicine, New York, New York, USA.
³⁰ Department of Microbiology, NewYork University Grossman School of Medicine, New York, New York, USA.
³¹ Division of Hospital Medicine, Department of Pediatrics, Vanderbilt University School of Medicine and the Monroe Carell Jr Children's Hospital at Vanderbilt University Medical Center, Nashville, Tennessee, USA.
³² Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina, USA.

PMID: 37843115
PMCID: PMC10578051
DOI: 10.1093/cid/ciad565

Review

Priorities and Progress in Gram-positive Bacterial Infection Research by the Antibacterial Resistance Leadership Group: A Narrative Review

Sarah B Doernberg et al. Clin Infect Dis. 2023.

. 2023 Oct 16;77(Suppl 4):S295-S304.

doi: 10.1093/cid/ciad565.

Authors

Collaborators

Antibacterial Resistance Leadership Group:
Robin Patel, Heather King, Tori Kinamon, Weixiao Dai, Holly Geres, Nancie Deckard, Carl Schuler, Ivra Bunn, Shrabani Sharma, Cathy Wickward, Jason Waller, Holly Wilson, Maureen Mehigan, Varduhi Ghazaryan, Erica Raterman, Tamika Samuel, Marina Lee

Affiliations

¹ Division of Infectious Diseases, Department of Medicine, University of California, SanFrancisco, California, USA.
² Division of Infectious Diseases, Department of Medicine, Houston Methodist Hospital, Houston, Texas, USA.
³ Center for Infectious Diseases, Houston Methodist Research Institute, Houston, Texas, USA.
⁴ Department of Medicine, Weill-Cornell Medical College, New York, New York, USA.
⁵ Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
⁶ Department of Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, NewYork, New York, USA.
⁷ Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
⁸ Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
⁹ Tufts University School of Medicine, Medford, Massachusetts, USA.
¹⁰ Division of Pediatric Infectious Diseases, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
¹¹ Vanderbilt Vaccine Research Program, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
¹² Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
¹³ Department of Biostatistics, George Washington University, Washington, District of Columbia, USA.
¹⁴ Division of Infectious Diseases, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA.
¹⁵ Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St Louis, Missouri, USA.
¹⁶ Biostatistics Center, George Washington University, Rockville, Maryland, USA.
¹⁷ Division of Infectious Diseases, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
¹⁸ Department of Laboratory Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
¹⁹ Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA.
²⁰ Division of Allergy and Infectious Diseases, University of Washington, Seattle, Washington, USA.
²¹ Department of Pharmacy Practice, Albany College of Pharmacy and Health Sciences, Albany, New York, USA.
²² Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California, USA.
²³ Division of Infectious Diseases, Lundquist Institute at Harbor-UCLA Medical Center, Torrance, California, USA.
²⁴ Instituto de Ciencias e Innovación en Medicina, Facultad de Medicina Clinica Alemana, Universidad del Desarrollo, Santiago, Chile.
²⁵ Multidisciplinary Initiative for Collaborative Research on Bacterial Resistance, Santiago, Chile.
²⁶ Division of Infectious Diseases, Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA.
²⁷ Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, Connecticut, USA.
²⁸ Pharmacometrics Center of Excellence, College of Pharmacy, Midwestern University, Downers Grove, Illinois, USA.
²⁹ Division of Infectious Diseases, Department of Medicine, New York University Grossman School of Medicine, New York, New York, USA.
³⁰ Department of Microbiology, NewYork University Grossman School of Medicine, New York, New York, USA.
³¹ Division of Hospital Medicine, Department of Pediatrics, Vanderbilt University School of Medicine and the Monroe Carell Jr Children's Hospital at Vanderbilt University Medical Center, Nashville, Tennessee, USA.
³² Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina, USA.

PMID: 37843115
PMCID: PMC10578051
DOI: 10.1093/cid/ciad565

Abstract

The Antibacterial Resistance Leadership Group (ARLG) has prioritized infections caused by gram-positive bacteria as one of its core areas of emphasis. The ARLG Gram-positive Committee has focused on studies responding to 3 main identified research priorities: (1) investigation of strategies or therapies for infections predominantly caused by gram-positive bacteria, (2) evaluation of the efficacy of novel agents for infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci, and (3) optimization of dosing and duration of antimicrobial agents for gram-positive infections. Herein, we summarize ARLG accomplishments in gram-positive bacterial infection research, including studies aiming to (1) inform optimal vancomycin dosing, (2) determine the role of dalbavancin in MRSA bloodstream infection, (3) characterize enterococcal bloodstream infections, (4) demonstrate the benefits of short-course therapy for pediatric community-acquired pneumonia, (5) develop quality of life measures for use in clinical trials, and (6) advance understanding of the microbiome. Future studies will incorporate innovative methodologies with a focus on interventional clinical trials that have the potential to change clinical practice for difficult-to-treat infections, such as MRSA bloodstream infections.

Keywords: antibacterial agents; antibacterial resistance; gram-positive bacterial infections; methicillin-resistant Staphylococcus aureus; vancomycin-resistant enterococci.

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Conflict of interest statement

Potential conflicts of interest. All authors report funding support from the ARLG of the NIH and the NIAID (UM1AI104681). S. B. D. reports grants or contracts paid to her institution from Gilead, Pfizer, F2G, Regeneron, Chan Zuckerberg Biohub, and NIAID/NIH; consulting fees paid directly to her from Genentech and Janssen/Johnson & Johnson (J&J); travel and meeting support from the Infectious Diseases Society of America (IDSA) to speak at IDWeek; a patent (US20100143379A1) for Mif agonists and antagonist and therapeutic uses thereof; a leadership role on the IDSA Antibacterial Resistance Committee, California Department of Public Health Hospital Acquired Infections Advisory Committee, and ARLG Innovations Group, Laboratory Center, Mentorship Committee, Gram-positive Committee, and Immunosuppressed Host Group; and payment directly to her for clinical events committee/adjudication committee participation from Shionogi, Basilea, and the Duke Clinical Research Institute.D. R. A. reports funding support from ContraFect and a leadership role on the ARLG Gram-positive Committee. A. B. reports funding support from the ARLG Early Faculty Seedling Award (NIAID UM1AI104681) and consulting fees from Roche. H. W. B. reports royalties from the Sanford Guide; consulting fees from the Sanford Guide, Antimicrobial Agents and Chemotherapy/American Society for Microbiology (ASM), and ID Clinics of North America/Elsevier; honoraria for Grand Rounds at Temple University; travel and meeting support for an IDWeek Lecture; membership as a voting member on the Presidential Advisory Council on Combating Antibiotic-Resistant Bacteria; and membership on the Board of Trustees at the College of the Holy Cross. B. C. reports grants or contracts paid to his institution from Moderna Vaccines and Merck Vaccines; royalties from UpToDate; consulting fees from Cowen Investments, Pfizer, Moderna, GSK, and Sanofi; payment as a medicolegal expert with multiple law firms; participation on the data and safety monitoring board (DSMB) or advisory board for Affinivax and GSK; and a leadership role as president of the Pediatric Infectious Diseases Society. S. E. C. reports grants or contracts paid to her institution from the Agency for Healthcare Research and Quality (AHRQ), the Centers for Disease Control and Prevention (CDC), the Patient-Centered Outcomes Research Institute, and the US Food and Drug Administration (FDA); consulting fees paid directly to her from the Duke Clinical Research Institute; participation on a DSMB for Debiopharm; and leadership roles as a board member of the National Foundation for Infectious Diseases and Globarl Antibiotic Research and Development Partnership North America (GARDP-NA). S. R. E. reports grants from the NIAID/NIH and De Gruyter (Editor-in-Chief for Statistical Communications in Infectious Diseases); royalties from Taylor & Francis; consulting fees from Genentech, AstraZeneca, Takeda, Microbiotix, J&J, Endologix, ChemoCentryx, Becton Dickinson, Atricure, Roviant, Neovasc, Nobel Pharma, Horizon, International Drug Development Institute (IDDI), SVB Leerink, Medtronic, Regeneron, Wake Forest University, Recor, Janssen, and IDDI; payments from Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION); meeting support from the FDA, Deming Conference on Applied Statistics, Clinical Trial Transformation Initiative, Council for International Organizations of Medical Sciences, International Chinese Statistical Association Applied Statistics Symposium, and Antimicrobial Resistance and Stewardship Conference; board member participation for the NIH, Breast International Group, University of Pennsylvania, Washington University, Duke University, Roche, Pfizer, Takeda, Akouos, Apellis, Teva, Vir, DayOneBio, Alexion, Tracon, Rakuten, AbbVie, Nuvelution, Clover, FHI Clinical, Lung Biotech, SAB Biopharm, Advantagene, Candel, and Novartis; and board positions with the American Statistical Association, Society for Clinical Trials, and Frontier Science Foundation. V. G. F. reports personal consulting fees from Novartis, Debiopharm, Genentech, Achaogen, Affinium, The Medicines Co, MedImmune, Bayer, Basilea, Affinergy, Janssen, ContraFect, Regeneron, Destiny, Amphliphi Biosciences, Integrated Biotherapeutics, C3J, Armata, Valanbio, Akagera, Aridis, Roche, and Pfizer; grants from NIH, MedImmune, Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Merck, Medical Biosurfaces, Locus, Affinergy, ContraFect, Karius, Genentech, Regeneron, Deep Blue, Basilea, and Janssen; royalties from UpToDate; stock options from Valanbio and ArcBio; honoraria from the IDSA for his service as Associate Editor of Clinical Infectious Diseases; travel support from ContraFect to the 2019 European Congress of Clinical Microbiology and Infectious Diseases (ECCMID); and a sepsis diagnostics patent pending. S. A. F. reports grant or contracts from NIH (P50HD103525, U01AL116400, R21AI176063) and AHRQ (R01 HS024269), honoraria from ARLG, and provision of Clorox wipes for a clinical research study. B. J. K. reports grants from CDC and NIAID; honoraria from ARLG; and leadership roles in the CDC Microbiome Working Group, IDSA Journal Club, and ARLG. T. H. reports consulting fees from Tanabe-Mitsubishi Pharma and honoraria from Duke University and Cancer and Chemo Therapy. T. P. L. reports grants paid to his institution from Wockhardt; grants paid directly to him from Paratek, Cidara, Biofire Diagnostics, and Merck; payment directly to him for lectures from Shionogi, Ferring, Seres, and Melinta; consulting fees paid directly to him from AbbVie, Cidara Therapeutics, Ferring, ICPD, Genentech, J&J, Melinta, Merck, Roche, Shionogi, Spero, Venatrox, La Jolla, Seres, Paratek, GSK, and DoseMe; and payment for the development of educational presentations from the Mayo Clinic. L. G. M. reports grants or contracts from Merck, ContraFect, Paratek, Medline, and GSK. J. M. M. reports grants from Asociación Nacional de Investigación y Desarrollo, Fondo Nacional de Desarrollo Científico y Tecnológico FONDECYT (grant number 1211947). B. S. reports advisory board fees paid directly to him from Basilia. T. T. T. reports grants from NIH paid to her institution; travel and meeting support from IDSA; and a leadership role on the IDWeek Planning Committee and a role as a Gulf Coast Consortium Cluster Reviewer (both unpaid). N. A. T. reports grants from CDC and PDI, Inc; and consulting fees from Techspert. D. J. W. reports grants paid to his institution from CDC and NIH/NIAID; a leadership role on the IDSA Childhood Pneumonia Guidelines Committee; and receipt of equipment from bioMérieux for procalcitonin assays for an observational study. T. L. H. reports grants from Karius and NIH; royalties from UpToDate; consulting fees from Aridis, Pfizer, Lysovant, and Affinivax; and participation on a DSMB for the SNAP Trial and the advisory board for Basilea. C. A. A. reports grant funding to their institution from NIH/NIAID (1 Po1 AI152999, R01AI148342, R01 AI346337, T32 AI141349, K24 Ai121296, U19 AI44297, R01 AI150685, and R21 AI151536), MeMed Diagnostics Ltd, Entasis Therapeutics, Merck Pharmaceuticals, and Harris County Public Health; royalties paid to them from UpToDate; reimbursement from IDSA for attending IDWeek as a speaker and part of the organizing committee; reimbursement from ASM to attend ASM Microbe as a speaker; reimbursement from the Society for Healthcare Epidemiology of America (SHEA) to attend SHEA as a speaker; reimbursement from the European Society for Clinical Microbiology and Infectious Diseases to attend ECCMID as a speaker; reimbursement from Mérieux Foundation to attend ICARE course as faculty; reimbursement from Sociedad Chilea de Infectiologia, Sociedad Colombiana de Infectologia, Pan American Society for Infectious Diseases, and Brazilian Society for Infectious Diseases to attend the annual meeting and act as a speaker; was an unpaid participant on a DSMB with the World Health Organization and Antibacterial Pipeline Advisory Group; received payment for participation with the NIH Grant Review Study Sections; was a voluntary member of the board of directors of IDSA; and is the Editor-in-Chief of Antimicrobial Agents and Chemotherapy. B. E. M. reports royalties from UpToDate for online chapters; consulting fees from JRD, LLC (J&J), PPD Development, LP (GSK0 and Basilea Pharmaceutical International Ltd); participation on a DSMB with NIH Therapeutic and Prevention; and held the position of Governor of the Academy with the American Academy of Microbiology. C. L. reports grant payments to their institutions from NIAID/NIH (1R01AI151038-01) and Pfizer. M. H. S. reports advisory board fees from DoseMe; consulting fees from GSK and Entasis; and has an issued patent US10688195B2. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Figures

**Figure 1.**
Antibacterial Resistance Leadership Group gram-positive research priorities.

**Figure 2.**
Dalbavancin as an Option for Treatment of *Staphylococcus aureus* Bacteremia (DOTS) study schematic. Figure used under a Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/) from Turner et al [46].

**Figure 3.**
Desirability of outcome ranking analysis by vancomycin area under the curve quintiles. Bottom quintile, 94.3–389.8; second quintile, >389.8–515.7; third quintile, >515.7–620.8; fourth quintile, >620.8–757.4; top quintile, >757.4–1755.0. Abbreviations: AKI, acute kidney injury; AUC, area under the curve; DOOR, desirability of outcome ranking analysis; Q, quintile; TF, treatment failure; TS, treatment success. Figure used with permission from Lodise et al [5].

**Figure 4.**
Sample study schematic for validation and interventional studies using biomarkers to personalize antibiotic management for *Staphylococcus aureus* bloodstream infections. Abbreviations: DOOR, desirability of outcome ranking; mNGS, metagenomic next-generation sequencing; SAB, *Staphylococcus aureus* bacteremia; Tx, treatment; UD, undetectable. Figure used with permission from Mourad A, Fowler VG Jr, Holland TL. Which trial do we need? Next-generation sequencing to individualize therapy in *Staphylococcus aureus* bacteraemia. *Clin Microbiol Infect* 2023; 29:955–58.

See this image and copyright information in PMC

References

1. Antimicrobial Resistance Collaborators . Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet 2022; 399:629–55. - PMC - PubMed
1. Doernberg SB, Lodise TP, Thaden JT, et al. . Gram-positive bacterial infections: research priorities, accomplishments, and future directions of the Antibacterial Resistance Leadership Group. Clin Infect Dis 2017; 64(Suppl_1):S24–9. - PMC - PubMed
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Priorities and Progress in Gram-positive Bacterial Infection Research by the Antibacterial Resistance Leadership Group: A Narrative Review

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Priorities and Progress in Gram-positive Bacterial Infection Research by the Antibacterial Resistance Leadership Group: A Narrative Review

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Abstract

Conflict of interest statement

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