BRIDGING THE GAP
Antibiotic resistance represents one of the greatest global threats to human health, causing approximately 700,000 deaths per year. Due to increasing rates of multidrug-resistance, deaths attributable to antibiotic resistant infections are projected to increase to 10 million annually by 2050, surpassing cancer as the leading cause of death worldwide.
The Britt Lab works at the interface of microbiology, immunology, and systems biology to discover novel therapeutic strategies for the mangement of “superbug” infections, using in vitro, ex vivo, and computational approaches. Our mission is to improve patient care, prevent harm, and preserve the miracle of antibiotic therapy.
Clinical Outcomes Research
multidrug-resistant Gram-negative infection
We utilize national clinical databases to perform large-scale pharmacoepidemiologic and comparative effectiveness analyses to identify optimal treatments for carbapenem-resistant Gram-negative infections. In a large analysis of patients with carbapenem-resistant Enterobacteriaceae bloodstream infection (CRE-BSI), we found significantly improved survival with polymyxin B therapy compared to colistin and with polymyxin/carbapenem combination therapy compared to polymyxin monotherapy (Britt, et al. 2018). Other significant work in this area includes a single-center comparative effectiveness analysis of antibiotics to treat carbapenem-resistant Pseudomonas aeruginosa sepsis (Britt, et al. 2018) as part of a project led by Dr. Scott Micek (Co-PI, St. Louis College of Pharmacy) and Dr. Marin Kollef (Co-PI, Washington University in St. Louis School of Medicine). We are continuing to investigate the comparative effectiveness and safety of antibiotic treatments for multidrug-resistant Gram-negative infection.
Vancomycin-resistant Enterococcus Infection
Vancomycin-resistant Enterococcus bloodstream infections (VRE-BSI) are frequently encountered in clinical practice and are associated with significant mortality (35%). Utilizing national clinical databases, we conducted a retrospective multicenter study comparing clinical outcomes between daptomycin and linezolid (Britt, et al. 2015). As part of a project led by Dr. Molly Steed (University of Kansas School of Pharmacy) and Dr. Emily Potter (VA Eastern Kansas Healthcare System), we were the first group to find that daptomycin improved outcomes compared to linezolid for the treatment of these high-mortality infections (Britt, et al. 2015). Furthermore, we uncovered that outcomes could be improved even among patients who initially received linezolid and switched to daptomycin therapy (Britt, et al. 2017). Subsequently, we compared daptomycin dosing strategies for VRE-BSI, and were the first to find that high-dose daptomycin (10 mg/kg) improved survival compared to medium (8 mg/kg) and standard (6 mg/kg) intensities (Britt, et al. 2017). Collectively, these efforts have shown that optimizing antibiotic therapy for VRE-BSI can lower mortality from 35% to 20%. Furthermore, we recently collaborated on a study used to define daptomycin AUC/MIC thresholds for efficacy (Avery et al., 2018), which were used by the Clinical and Laboratory Standards Institute (CLSI) to revise susceptibility breakpoints.
Staphylococcus aureus bacteremia
Staphylococcus aureus bacteremia (SAB) is a severe infection with a high associated mortality rate. Vancomycin has been the mainstay of SAB treatment for many decades, but treatment failure is common despite seemingly appropriate therapy. In a project led by Dr. Molly Steed (PI, University of Kansas School of Pharmacy), we sought to identify microbiological characteristics that may influence clinical outcome, with a focus on minimum bactericidal concentration (MBC). As part of this effort, we found that vancomycin tolerance was associated with poorer clinical outcomes among patients with SAB, irrespective of methicillin susceptibility and antibiotic choice (Britt, et al. 2017). Therefore, vancomycin tolerance likely represents an important marker for failure of cell wall-active therapy. Furthermore, we explored the relationship between vancomycin exposure and MBC, finding that vancomycin area under the curve (AUC)/MBC ratio was a more reliable predictor of mortality than AUC/MIC (Britt, et al. 2017).
C. difficile infection
Clostridium difficile is the most common cause of healthcare-associated infectious diarrhea and is associated with significant morbidity and mortality. We have conducted multiple investigations evaluating therapies for severe, complicated, and recurrent C. difficile infection (CDI). We demonstrated a potential role for the use of tigecycline in patients with severe disease who are unable to tolerate oral therapies and are too ill for surgical intervention (Britt, et al. 2014). Current efforts are focused on prospectively evaluating the efficacy and safety of bezlotoxumab, a monoclonal antibody to C. difficile toxin B, for the prevention of CDI recurrence in high-risk populations (NCT03880539).
Human immunodeficiency virus Infection
One of the most significant public health achievements of the last quarter-century has been the introduction of highly active antiretroviral therapy (HAART) for human immunodeficiency virus (HIV) infection, which has led to profound improvements in HIV-associated mortality. Secondary to this increased life expectancy, persons living with HIV (PLWH) are now more commonly succumbing to the same non-infectious complications that plague uninfected individuals. In a study led by Dr. Nimish Patel (PI, University of California-San Diego), we have evaluated the impact of drug-drug interactions, polypharmacy, and pill burden on achievement of cardiometabolic disease goals among HIV-infected patients (Malek, et al. 2017 and Ahmed, et al. 2019). As part of this ongoing collaboration, we are continuing to study elimination of hepatitis C virus (HCV) in HIV-coinfected patients.
Transplant infectious diseases
Urinary tract infection (UTI) is the most common infectious complication following kidney transplantation. In collaboration with Dr. Timothy Horwedel (PI, Barnes-Jewish Hospital) and Dr. Daniel Brennan (Johns Hopkins Hospital, formerly Washington University in St. Louis School of Medicine), we uncovered that recurrent UTIs were associated with significantly poorer graft and patient outcomes compared to non-recurrent UTI and no UTI (Britt, et al. 2017). We are continuing to evaluate the comparative effectiveness of treatment options for infections in immunosuppressed patient populations.
Microbiology and Immunology
IMMUNOMODULATION AND HOST-PATHOGEN INTERACTIONS IN SEPSIS
Despite significant advances in medical care, sepsis and septic shock continue to be major causes of death in intensive care units (ICUs). There is increasing evidence to support the short- and long-term detrimental effects of immune cell dysregulation in sepsis. We are involved in multiple projects aimed at defining immunophenotypes, biomarkers, and immunoadjuvant therapies for sepsis.
We work in close collaboration with the laboratory of Dr. Molly Steed as part of the University of Kansas Medical Center Antimicrobial Pharmacokinetics/Pharmacodynamics Translational Research Laboratory (ASTRAL), which specializes in the application of in vitro PK/PD models of infection to optimize the use of antimicrobial agents for the treatment of infections due to multidrug-resistant organisms (MDROs). Current collaborative efforts are focused on evaluating the activity of novel treatment regimens against a variety of multidrug-resistant Gram-positive and Gram-negative pathogens.
Infectious Diseases Epidemiology
multidrug-resistant Gram-negative infection
Utilizing national clinical databases, we recently characterized the changing epidemiology of carbapenem-resistant Enterobacteriaceae bloodstream infections (CRE-BSI) , demonstrating increased incidence of infection due to Enterobacter and Proteus species. We have shown that decreases in the incidence of CRE-BSI are attributable to a national infection control initiative. In a single-center retrospective study, we uncovered a similar shifting burden disease in carbapenem-resistant Gram-negative sepsis (Britt, et al. 2018).
VANCOMYCIN-RESISTANT ENTEROCOCCUS INFECTION
We recently described a decrease in the incidence of bloodstream infections due to vancomycin-resistant Enterococcus (VRE) (Britt, et al. 2017). In a subsequent analysis, we demonstrated that decreasing rates of infections are temporally related to the institution of a national infection control initiative. Current efforts are underway to further evaluate the transmission dynamics of VRE across a variety of healthcare settings.