Shields Laboratory

The Shields lab works to design individualized approaches to antimicrobial therapy that prevent and treat infections due to drug-resistant pathogens.

The objective is to identify and validate antibiotic combination regimens that effectively eradicate Klebsiella pneumoniae carbapenemase producing K. pneumoniae (KPC-Kp) and suppress the emergence of ceftazidime-avibactam resistance. Utilizing sophisticated hollow-fiber infection models (HFIM) and ultrahigh-performance liquid chromatography-mass spectrometry (UHPLC-MS) techniques that Shields developed through his K08 training period to simulate humanized exposures of antibiotics and quantify resistance suppression over time. Using these data, the Shields lab will use mathematical modeling to design optimized treatment regimens against KPC-Kp infections, testing combination regimens in a fully-factorial HFIM and murine infection model before translating results to the patient bedside. The Shields lab is devoted to the care of patients with KPC-Kp infections.

Contribution to Science

Epidemiology and clinical outcomes of patients infected by multidrug-resistant pathogens

Infections due to multidrug-resistant hospital superbugs are associated with disproportionately high rates of death. The backbone of our translational research program is a careful description of patient cases that we use to guide laboratory investigations. We investigate emergence of resistance from clinical isolates collected from hospitalized patients across diverse bacterial species or within a population of bacteria infecting a patient. Our clinical databases are able to link the treatment outcomes of patients with critical information about the molecular characteristics and antibiotic susceptibility of infecting bacterial strains.

Clinical and molecular features of novel drug resistance against CRE

Ceftazidime-avibactam (CAZ-AVI), meropenem-vaborbactam (MER-VAB), and imipenem-relebactam (IMI-REL) are new antibiotic agents with similar, but distinct characteristics against carbapenem-resistant Enterobacteriaceae (CRE). We have described the first cases of treatment-emergent resistance due to mutations in β-lactamase or porin genes through whole-genome sequencing and molecular validation studies. Our lab continues to investigate new mechanisms by which CRE develop resistance to CAZ-AVI, MER-VAB, and IMI-REL, and to identify strategies that effectively suppress the emergence of resistance. We pursue these objectives with innovative in vitro models that simulate humanized exposures of these antibiotics over time. The resulting data are translated to provide timely, clinically-relevant data on optimized treatment in the face of a rapidly changing CRE landscape.

Navigating complex antibiotic resistance mechanisms to define optimal treatment of multidrug-resistant Pseudomonas aeruginosa infections

Pseudomonas aeruginosa is a common nosocomial pathogen with a unique ability to evade antibiotic treatment. Our lab has uncovered new mechanisms by which the organism has evolved to develop resistance to the newest antibiotics. Importantly, we have also discovered that resistance to one antibiotic may result in collateral sensitivity to another antibiotic or antibiotic class. In designing effective therapeutic regimens we use the knowledge gained through these investigations in order to leverage complex mechanisms to achieve better outcomes for patients and employ the most recently approved antibiotics judiciously. To hear more about how our research has made important advancements in the field, please click here.

Real world comPaRative EffeCtivEness studies for Drug-rEsistaNT infections in the United States (PRECEDENT)

While our field has witnessed the rebirth of antibiotic discovery in the last decade, critical real-world evidence is missing. This is particularly true for the comparative-effectiveness of newly-approved antibiotics used to treatment patients infected with multidrug-resistant pathogens. To address these important knowledge gaps, Dr. Shields and colleagues have established the PRECEDENT network, a consortium of leading medical centers in the United States. The overarching goal of the network is to define optimal treatment pathways for patients infected by multidrug-resistant pathogens. To accomplish this we have conducted several multicenter studies to compare the clinical and microbiological effectiveness of varying treatment approaches. Examples of ongoing studies include:

• Ceftazidime-Avibactam versus Ceftolozane-Tazobactam for multidrug-resistant Pseudomonas aeruginosa infections in the United States (CACTUS)
• Effectiveness of iMIpenem-Relebactam for multidrug-resistant Pseudomonas AeruGinoa in reatment and bloodstream infections in the United States (MIRAGE)
• CefiderOcol treatment Versus ceftolozane/tazobactam for the treatment of pneumonia and/or bloodstream InfeCtions due to multidrug-resistant PsEudomonas aeruginosa (CONVINCE)
• Optimizing escalation: Ceftolozane/tazobactam versus treatment with traditional anti-pseudomonal β-lactams for pneumonia or bloodstream infections due to MDR P. aeruginosa (STEWARDS).

To learn more about this growing research network, please visit our website at https://www.precedentnetwork.com.