About

Brian Werth is an Associate Professor in the Department of Pharmacy at the University of Washington School of Pharmacy. He received his PharmD from the University of New Mexico and completed a pharmacy practice residency at The Queen's Medical Center in Honolulu, HI. Following this, he completed an Infectious Diseases Pharmacotherapy Fellowship at Wayne State University in Detroit, MI. Dr. Werth joined the University of Washington Department of Pharmacy as an Assistant Professor in 2013. His research focuses on antimicrobial resistance and the pharmacokinetics and pharmacodynamics of antimicrobials. His interdisciplinary translational research program is primarily dedicated to understanding the mechanisms of cross-resistance among glycopeptides, lipopeptides, and lipoglycopeptides in Methicillin-Resistant Staphylococcus aureus (MRSA). His work includes investigating mechanisms of resistance to antibiotics, antimicrobial pharmacodynamics, and antimicrobial resistance, cross-resistance, and synergy. Dr. Werth also teaches courses such as Pharmacotherapeutics III, covering disorders of the cardiovascular, pulmonary, renal, and endocrine systems.

Research topics

• Microbiology
• Biology
• Genetics
• Medicine
• Pediatrics
• Nursing
• Economics
• Pharmacology
• Family medicine
• Emergency medicine
• Socioeconomics
• Environmental health

Selected publications

• Emergence of Dalbavancin, Vancomycin, and Daptomycin Cross-resistance in MRSA During Long-term LVAD Suppression With Vancomycin Followed by Dalbavancin: Genomic Insights and Synergy With Cefadroxil

  Open Forum Infectious Diseases · 2026-02-13

  articleOpen accessSenior author

  Abstract We present a case in which vancomycin and dalbavancin exposure preceded emergence of nonsusceptibility to dalbavancin, vancomycin, and daptomycin in a strain of methicillin-resistant Staphylococcus aureus in the setting of a left ventricular assist device (LVAD) infection. We characterized 6 related but genetically unique isolates collected over more than 1 year of recurrent therapy and found that the most resistant isolate acquired multiple walK-related mutations, which has been previously implicated in dalbavancin resistance with vancomycin and daptomycin cross-resistance. Using time-kills at subinhibitory exposures, we found that cefadroxil is synergistic with dalbavancin against the susceptible and resistant strains. This is the first report of dalbavancin nonsusceptibly associated with an LVAD infection, but dalbavancin resistance has been documented previously in association with treatment of endovascular infections. Combination therapy with synergistic and orally bioavailable agents like cefadroxil may be a reasonable strategy to enhance activity and possibly diminish emergence of resistance to dalbavancin.

  PublisherDOI

• Leveraging Change Management Principles to Implement Computer-Based Assessments in a PharmD Program

  American Journal of Pharmaceutical Education · 2025-11-01

  articleOpen access
  PublisherDOI

• Clozapine and tuberculosis treatment: a case report and literature review

  Frontiers in Psychiatry · 2025-07-09

  articleOpen access

  Introduction: To date, clozapine is the only antipsychotic approved by the United States Food and Drug Administration (FDA) for the management of treatment-resistant schizophrenia. People with serious mental illness are at higher risk of developing tuberculosis and have worse tuberculosis recovery outcomes compared to the general population. First-line regimens for acute tuberculosis often include rifamycins and isoniazid, both of which impact clozapine metabolism and levels through induction or inhibition of the hepatic cytochrome P450 (CYP450) enzyme system. There is limited evidence, mostly from case reports, to guide clinicians in managing clozapine alongside anti-tuberculosis therapy (ATT). Literature review: = 3), the ATT regimen included both rifampicin, a CYP450 inducer, and isoniazid, a CYP450 inhibitor. We also review pharmacokinetic properties of rifampicin and the potential impact of rifamycin-based regimens on clozapine metabolism and levels. Case presentation: We present the case of a 35-year-old prescribed clozapine for 4 years prior to being diagnosed with pulmonary tuberculosis. The patient continued clozapine and was closely followed in both the inpatient and outpatient settings while completing a 6-month course of rifampicin, isoniazid, pyrazinamide, and ethambutol. During ATT, the patient had clozapine and norclozapine levels measured at least once monthly and maintained stability in their psychiatric symptoms through adjustment of clozapine and adjunctive antipsychotic dosages. Conclusion: Our case supports previous reports that ATT can influence clozapine levels. Clozapine dose adjustments will likely be required to maintain clinical stability and prevent adverse effects, but the management appears to be patient-specific. We recommend closely monitoring patients' clinical status and clozapine levels during and after ATT to optimize outcomes.

  PublisherOA PDFDOI

• Simulated exposures of oritavancin in <i>in vitro</i> pharmacodynamic models select for methicillin-resistant <i>Staphylococcus aureus</i> with reduced susceptibility to oritavancin but minimal cross-resistance or seesaw effect with other antimicrobials

  Journal of Antimicrobial Chemotherapy · 2025-01-30 · 2 citations

  articleOpen access1st authorCorresponding

  BACKGROUND: Dalbavancin exposures select for VAN and daptomycin cross-resistance in Staphylococcus aureus often by walK-related mutations. Oritavancin is another long-acting lipoglycopeptide, but its proclivity to select for cross-resistance is unknown. The objective of this study was to determine if post-distributional pharmacokinetic oritavancin exposures select for meaningful susceptibility changes in S. aureus. METHODS: We simulated average post-distributional, free-drug exposures of oritavancin 1200 mg IV once (fCmax 11.2 µg/mL; β-elimination t1/2 13.4 h; γ-elimination t1/2 245 h) in an in vitro pharmacodynamic model for 28 days against five S. aureus including four MRSA. Samples were taken daily for colony enumeration and resistance screening. Susceptibility testing was repeated on isolates from resistance screening plates against oritavancin, vancomycin, daptomycin, dalbavancin and 6 beta-lactams with varying penicillin-binding protein affinities. RESULTS: Tested oritavancin exposures were bactericidal against 5/5 strains for 2-17 days before regrowth of less-susceptible subpopulations occurred. Isolates with reduced susceptibility to oritavancin were detected as early as 5 days, but the MIC increased above the susceptibility breakpoint (>0.125 mg/L) in 4/5 strains eventually. Vancomycin and daptomycin MICs increased by 2- to 8-fold but did not exceed the susceptibility breakpoints in most isolates. β-lactam MICs were largely unchanged among the recovered isolates with reduced oritavancin susceptibility. Mutations were diverse but often involved purR with 13 unique variants identified among 4/5 strains. CONCLUSIONS: Oritavancin-selected resistance was primarily associated with purR mutation and less frequently associated with cross-resistance and walK mutation than dalbavancin-selected resistance in similar strains and conditions. The reason for this is unclear but may stem from differences in the mechanism(s) and divergent mutational pathways.

  PublisherOA PDFDOI

• Integrated Analysis for Identification, Phenotyping, and Antimicrobial Susceptibility Testing (AST) of Bacteria Using Mass Spectrometry, Machine Learning, and Multi-omics Analysis

  2023-10-06

  book-chapter

  Antimicrobial resistance (AMR) is gradually becoming a global public health problem. Rapid and cost-effective identification of AMR bacteria is the key to guiding the therapeutic management of bacterial infections/diseases. Mass spectrometry (MS) has been progressively adopted in clinical laboratories, especially for species identification. A series of supervised machine learning models have been systematically studied and have been shown to have great potential in strain-level typing. In the meantime, metabolites and lipids have been proven to facilitate pathogen typing, especially for differentiating SNP variants. More strikingly, the integration of multi-omics data has moved MS-based bacterial typing beyond identification and antimicrobial susceptibility testing (AST) to understanding the molecular mechanisms of AMR evolution.

  PublisherDOI

• Elucidating the Impact of Bacterial Lipases, Human Serum Albumin, and FASII Inhibition on the Utilization of Exogenous Fatty Acids by <i>Staphylococcus aureus</i>

  bioRxiv (Cold Spring Harbor Laboratory) · 2023-06-29 · 2 citations

  preprintOpen access

  ABSTRACT Staphylococcus aureus only synthesizes straight-chain or branched-chain saturated fatty acids (SCFAs or BCFAs) via the type II fatty acid synthesis (FASII) pathway, but as a highly adaptive pathogen, S. aureus can also utilize host-derived exogenous fatty acids (eFAs), including SCFAs and unsaturated fatty acids (UFAs). S. aureus secretes three lipases, Geh, sal1, and SAUSA300_0641, which could perform the function of releasing fatty acids from host lipids. Once released, the FAs are phosphorylated by the fatty acid kinase, FakA, and incorporated into the bacterial lipids. In this study, we determined the substrate specificity of S. aureus secreted lipases, the effect of human serum albumin (HSA) on eFA incorporation, and the effect of FASII inhibitor, AFN-1252, on eFA incorporation using comprehensive lipidomics. When grown with major donors of fatty acids, cholesteryl esters (CEs) and triglycerides (TGs), Geh was found to be the primary lipase responsible for hydrolyzing CEs, but other lipases could compensate for the function of Geh in hydrolyzing TGs. Lipidomics showed that eFAs were incorporated into all major S. aureus lipid classes and that fatty acid-containing HSA can serve as a source of eFAs. Furthermore, S. aureus grown with UFAs displayed decreased membrane fluidity and increased production of reactive oxygen species (ROS). Exposure to AFN-1252 enhanced UFAs in the bacterial membrane, even without a source of eFAs, indicating a FASII pathway modification. Thus, the incorporation of eFAs alters the S. aureus lipidome, membrane fluidity, and ROS formation, which could affect host-pathogen interactions and susceptibility to membrane-targeting antimicrobials. IMPORTANCE Incorporation of host-derived exogenous fatty acids (eFAs), particularly unsaturated fatty acids (UFAs), by Staphylococcus aureus could affect the bacterial membrane fluidity and susceptibility to antimicrobials. In this work, we found that Geh is the primary lipase hydrolyzing cholesteryl esters and, to a less extent, triglycerides (TGs) and that human serum albumin (HSA) could serve as a buffer of eFAs, where low levels of HSA facilitate the utilization of eFAs, but high levels of HSA inhibit it. The fact that the FASII inhibitor, AFN-1252, leads to an increase in UFA content even in the absence of eFA suggests that membrane property modulation is part of its mechanism of action. Thus, Geh and/or the FASII system look to be promising targets to enhance S. aureus killing in a host environment by restricting eFA utilization or modulating membrane property, respectively.

  PublisherOA PDFDOI

• Elucidating the impact of bacterial lipases, human serum albumin, and FASII inhibition on the utilization of exogenous fatty acids by <i>Staphylococcus aureus</i>

  mSphere · 2023-11-28 · 10 citations

  articleOpen access

  ABSTRACT Staphylococcus aureus only synthesizes straight-chain saturated fatty acids (SCFAs) or branched-chain saturated fatty acids via the type II fatty acid synthesis (FASII) pathway, but as a highly adaptive pathogen, S. aureus can also utilize host-derived exogenous fatty acids (eFAs), including SCFAs and unsaturated fatty acids (UFAs). S. aureus secretes three lipases, glycerol ester hydrolase (Geh), S. aureus lipase 1, and SAUSA300_0641, which could release fatty acids from host lipids. Once released, the FAs are phosphorylated by the fatty acid kinase and incorporated into the bacterial lipids. In this study, we determined the substrate specificity of S. aureus secreted lipases, the effect of human serum albumin (HSA) on eFA incorporation, and the effect of FASII inhibitor AFN-1252 on eFA incorporation using comprehensive lipidomics. When grown with major donors of fatty acids, cholesteryl esters (CEs) and triglycerides (TGs), Geh was found to be the primary lipase responsible for hydrolyzing CEs, but other lipases could compensate for the function of Geh in hydrolyzing TGs. Lipidomics showed that eFAs were incorporated into all major S. aureus lipid classes and that fatty acid-containing HSA can serve as a source of eFAs. Furthermore, S. aureus grown with UFAs displayed increased membrane fluidity and increased production of reactive oxygen species (ROS). Exposure to AFN-1252 enhanced UFAs in the bacterial membrane, even without a source of eFAs, indicating the inhibition of double bond reduction by FabI. Thus, the incorporation of eFAs alters the S. aureus lipidome, membrane fluidity, and ROS formation, which could affect host-pathogen interactions and susceptibility to membrane-targeting antimicrobials. IMPORTANCE Incorporation of host-derived exogenous fatty acids (eFAs), particularly unsaturated fatty acids (UFAs), by Staphylococcus aureus could affect the bacterial membrane fluidity and susceptibility to antimicrobials. In this work, we found that glycerol ester hydrolase (Geh) is the primary lipase hydrolyzing cholesteryl esters and, to a lesser extent, triglycerides and that human serum albumin (HSA) could serve as a buffer of eFAs, where low levels of HSA facilitate the utilization of eFAs but high levels of HSA inhibit it. The fact that the type II fatty acid synthesis (FASII) inhibitor, AFN-1252, leads to an increase in UFA content even in the absence of eFA suggests that membrane property modulation is part of its mechanism of action. Thus, Geh and/or the FASII system look to be promising targets to enhance S. aureus killing in a host environment by restricting eFA utilization or modulating membrane properties, respectively.

  PublisherDOI

• High-throughput analysis of lipidomic phenotypes of methicillin-resistant Staphylococcus aureus by coupling in situ 96-well cultivation and HILIC-ion mobility-mass spectrometry

  Analytical and Bioanalytical Chemistry · 2023-08-03 · 2 citations

  articleOpen access
  PublisherOA PDFDOI

• Emergence of Dalbavancin, Vancomycin, and Daptomycin Nonsusceptible <i>Staphylococcus aureus</i> in a Patient Treated With Dalbavancin: Case Report and Isolate Characterization

  Clinical Infectious Diseases · 2022-04-29 · 33 citations

  articleOpen accessSenior author

  A patient with end-stage renal disease received 2 doses of dalbavancin for methicillin-resistant Staphylococcus aureus (MRSA) arteriovenous fistula infection and presented 5 weeks later with infective endocarditis secondary to vancomycin, daptomycin, and dalbavancin nonsusceptible MRSA. Resistance was associated with walK and scrA mutations, reduced long-chain lipid content, and reduced membrane fluidity.

  PublisherOA PDFDOI

• Reporting behaviors and perceptions toward the National Healthcare Safety Network antimicrobial use (AU) and antimicrobial resistance (AR) modules

  Infection Control and Hospital Epidemiology · 2022-06-15 · 3 citations

  articleOpen access1st authorCorresponding

  Abstract Objectives: To identify characteristics of US health systems and end users that report antimicrobial use and resistance (AUR) data, to determine how NHSN AUR data are used by hospitals and health systems and end users, and to identify barriers to AUR reporting. Design: An anonymous survey was sent to Society of Infectious Diseases Pharmacists (SIDP) and Society for Healthcare Epidemiology of America (SHEA) Research Network members. Methods: Data were collected via Survey Monkey from January 21 to February 21, 2020. Respondent and hospital data were analyzed using descriptive statistics. Results: We received responses from 238 individuals across 43 US states. Respondents were primarily pharmacists (84%), from urban areas, (44%), from nonprofit medical centers (81%), and from hospitals with &gt;250 beds (72%). Also, 62% reported data to the AU module and 19% reported data to the AR module. Use of software for local AU or AR tracking was associated with increased reporting to the AU module (19% vs 64%) and the AR module (2% vs 30%) ( P &lt; .001 each). Only 36% of those reporting data to the AU module used NHSN AUR data analysis tools regularly and only 9% reported data to the AR module regularly. Technical challenges and time and/or salary support were the most common barriers to AUR participation cited by all respondents. Among those not reporting AUR data, increased local expectations to report and better software solutions were the most commonly identified solutions to increase AUR reporting. Conclusions: Efforts to increase AUR reporting should focus on software solutions and salary support for data-entry activities. Increasing expectations to report may incentivize local resource allocation to improve AUR reporting rates.

  PublisherOA PDFDOI

Recent grants

• Contribution of altered cell envelope metabolism to resistance to cell envelope-targeting antimicrobials in MRSA

  NIH · $3.5M · 2018–2028

• Resistance Selection Potential of the Long Acting Lipoglycopeptides Dalbavancin and Oritavancin

  NIH · $428k · 2018–2021

Frequent coauthors

• Michael J. Rybak

  Wayne State University

  68 shared

• George Sakoulas

  University of California, San Diego

  38 shared

• Joseph Pogliano

  University of California, San Diego

  20 shared

• Warren E. Rose

  20 shared

• Katie E. Barber

  University of Mississippi

  19 shared

• Ryan Tewhey

  Jackson Laboratory

  18 shared

• Libin Xu

  University of Washington

  14 shared

• Cortney E. Ireland

  Eugene Applebaum College of Pharmacy and Health Sciences

  13 shared

Education

• Other

  University of New Mexico