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A BI-WEEKLY PUBLICATION FROM THE CEDARS-SINAI CHIEF OF STAFF November 20, 2015 | Archived Issues

P & T Approvals, FDA Statement About Plavix

Pharmacy Focus

See highlights of the October meeting of the Pharmacy and Therapeutics Committee. Also, the U.S. Food and Drug Administration says that long-term use of Plavix does not change the risk of death for patients with heart disease.

» Read more


Meetings and Events


Grand Rounds

Click here to view upcoming grand rounds.


Upcoming CME Conferences

Click below to view a complete list of all scheduled Continuing Medical Education conferences.

CME Newsletter - November 2015 (PDF)  


Milestones

Viorica Ionut, MD, PhD, Ali Kashani, MD, and Arnold Klein, MD, have died.

» Read more

Innovation Challenge Selects 10 Semifinalists

innovation

As a part of the first MD/RN Patient Experience Innovation Challenge, more than 250 nurses and physicians came together last week to pitch collaborative solutions to improve the patient experience at Cedars-Sinai. After listening to an array of innovative ideas, the panel of six judges selected 10 semifinalist teams.

» Read more

Antimicrobial Stewardship Alerts in CS-Link

From Chris Ng, MD, Chief of Staff

In an effort to reduce antimicrobial resistance and improve patient safety, Cedars-Sinai is launching best practice alerts in CS-Link™ for patients receiving selected antibiotics for three or more days. Increasing rates of drug-resistant infections and a limited supply of new antibiotics have placed new emphasis on promoting the safe, efficient use of antibiotics at healthcare organizations across the nation.

» Read more

Building New Solutions for Patients - in a Weekend

gewertz

Startup Competition Is Part of Cedars-Sinai Initiative to Accelerate Innovation

It was a weekend of hard work and sleepless nights that began with about 35 entrepreneurs and startup enthusiasts — most of whom had just met — brainstorming about ways to improve healthcare. It ended with applause and high fives as seven teams pitched new business models they had designed during an intense 54 hours, with the goal of making life better for patients around the world.

» Read more

Cardiac Monitoring Policy Is Updated

In order to make beds with cardiac monitors available to more patients, Cedars-Sinai has adapted the 2004 American Heart Association cardiac monitoring guidelines for use as its policy concerning the utilization of cardiac monitoring of general medical-surgical adult inpatients.

» Read more

CS-Link Tip: Haiku Schedule Enhancement

If you look at your schedule on your phone, you will have noticed a change in Haiku. This enhancement allows you to see patients scheduled not only directly with you but also with other providers and resources as long as they are part of your multiprovider schedule.

» Read more

Viorica Ionut, Research Scientist, 1968-2015

Viorica Ionut

Viorica Ionut, MD, PhD, a research scientist in the Cedars-Sinai Diabetes and Obesity Research Institute and assistant professor of Biomedical Sciences, has died. She was 47. The cause was breast cancer. An expert on the role of incretins, or gut hormones, in glucose homeostasis, Ionut was a longtime collaborator of Richard Bergman, PhD, the institute's director. She also was a graduate of Cedars-Sinai's Clinical Scholars Program.

» Read more

Open Enrollment for Individual/Family Plans Runs Through Jan. 31

From Thomas M. Priselac, President and CEO

We are about to embark on the third annual open enrollment period for individual and family health insurance plans since the Affordable Care Act was signed into law. This does not impact those of you who are covered by Cedars-Sinai-sponsored health insurance plans through Anthem Blue Cross. If you receive questions from patients — or if you have friends or family members who purchase individual and family health insurance plan on their own — you can advise them that only certain plans cover care from Cedars-Sinai.

» Read more

Study Sheds Light on 'Superbug' Treatment

A new Cedars-Sinai study sheds light on how treatment of the "superbug" known as MRSA with certain antibiotics can potentially make patients sicker. The findings, published Nov. 11 in the journal Cell Host & Microbe, could have implications for managing the bug, a virulent form of the common staph infection that can be difficult to control. The study's key authors included George Liu, MD, PhD, Sabrina Mueller, PhD, and David Underhill, PhD.

» Read more

Innovation Challenge Selects 10 Semifinalists

Innovation Challenge 1

Twenty teams pitched their ideas to improve the patient experience at the Nov. 10 event.

As a part of the first MD/RN Patient Experience Innovation Challenge, more than 250 nurses and physicians came together last week to pitch collaborative solutions to improve the patient experience at Cedars-Sinai.

The challenge emerged from the MD/RN Collaborative, which brings together members of the clinical care team to enhance clinical quality, safety and experience. Through the challenge, teams from the MD/RN Collaborative were tasked with identifying solutions in technology, design, devices and process.

In the challenge's first event — inspired by the popular ABC TV show Shark Tank — 20 teams were selected to pitch their ideas to a panel of six judges on Nov. 10.

After listening to an array of innovative ideas, the judges selected 10 semifinalist teams:

Innovation Challenge 2
Among the physicians and nurses presenting solutions were Axel Rosengart, MD, PhD, (left) and Azure Chabot, BSN, RN.
  • Team REM Pros seeks to provide personalized patient care by encouraging patients to make three wishes on an electronic wrist "Wishband." By making these wishes, patients are encouraged to participate in their own care and to learn more about perioperative processes, treatment options and medications.
  • Team Moments of Genius created an incentive program that provides motivation, inspiration and confidence during the discharge process. Items given to patients throughout the process encourage engagement before being discharged.
  • Team Heart Throbs designed a one-touch communications-based app that allows patients to communicate with staff and family members through the touch of an iPad. The app is available in multiple languages, helping to resolve language barriers.
  • Team Uber-ful Care pitched a patient-centered mobile triage kiosk to help reduce wait times and direct patients to appropriate areas of care within 30 minutes. An additional concierge care application would provide car service options to patients. The innovation aims to improve experience, quality, value and efficiency.
  • Team CS Assist created a solution using a touch-enabled kiosk that helps families locate patients, as well as areas of interest on campus. An additional app allows patients to gain a sense of control and autonomy while in the hospital.
  • Team Interactive Book uses drawings and language to help communicate topics relevant to all aspects of patient care. The book is an instant resource for questions throughout the care process.
  • Team Ohm Patrol created the Tree of Life, an enhanced IV pole designed to personalize patient care by infusing medicine with imagination. This redesigned pole, in the shape of a tree, would provide additional patient education resources and would incorporate New Age technology with holistic care to create the "Art of Healing."
  • Team Heat Menders is a patient-friendly tablet application that assists patients with selecting meals based on dietary needs and cultural preferences. It is designed to enhance communication between the interdisciplinary team and patients.
  • Team Cedars Engage is an app to help streamline workflows while empowering patients and families to partner with their care team. This mobile-based platform aims to improve communication between patients, families and providers.
  • Team Body Shop supports quarterly "tune-ups" performed by the interdisciplinary team on inpatients in effort to decrease readmissions and medication-related adverse events.

The semifinalists will develop their prototypes for mock implementation during a pilot phase over the next several months. A challenge winner will be selected in June.

Innovation Challenge 3

A panel of Cedars-Sinai executive judges considered the teams' solutions and picked 10 semifinalist teams.

Innovation Challenge 4

Audience member Naomi Tashman, RN, took a cellphone photo of the action.

Innovation Challenge 5

A large, enthusiastic audience watched the proceedings.

Related stories:

Innovation Challenge Teams to Pitch Ideas Nov. 10

Contest Aims to Improve Patient Experience

Antimicrobial Stewardship Alerts in CS-Link

From Chris Ng, MD, Chief of Staff

In an effort to reduce antimicrobial resistance and improve patient safety, Cedars-Sinai is launching best practice alerts in CS-Link™ for patients receiving selected antibiotics for three or more days. Increasing rates of drug-resistant infections and a limited supply of new antibiotics have placed new emphasis on promoting the safe, efficient use of antibiotics at healthcare organizations across the nation. Although antibiotics can save lives, they can also lead to complications including drug reactions and other serious infections such as Clostridium difficile.

This "three-day alert" will be implemented in phases, beginning in four test-of-change units — 4 Northwest, 5 Northeast, 5 Southwest and 8 Southwest — on Nov. 17. It will launch housewide for vancomycin on Dec. 8. The alerts are meant to help clinicians appropriately modify empiric antibiotic regimens after additional clinical information becomes available.

As part of the alerts, clinicians who prescribe antibiotics will be prompted to indicate their plans to discontinue, modify or continue use on the third day of a patient's treatment.

If treatment is continued, clinicians will need to document their reasons for continued therapy. The alert will also include a reference link to the Cedars-Sinai empiric antibiotic treatment guidelines to assist with antibiotic selection. In some cases, clinicians may also be contacted by a pharmacist to discuss antimicrobial therapy.

Should you have any questions or concerns about this project, please contact the antimicrobial stewardship pharmacist at 310-433-8700, ext. 3-5352 or by pager 1462.

We appreciate your continued collaboration in keeping our patients safe by ensuring they receive no more and no less antibiotic treatment than necessary. We will be soliciting your feedback as we move forward with this initiative to help guide future antimicrobial stewardship interventions. We also encourage you to take advantage of the Centers for Disease Control and Prevention's resources on antimicrobial stewardship as it celebrates Get Smart About Antibiotics Week next week.

Thank you for your support of this critical patient safety initiative.

Building New Solutions for Patients - in a Weekend

Startup Gewertz 480px

Bruce L. Gewertz, MD, Cedars-Sinai surgeon-in-chief and chair of the Department of Surgery, (right) conferred with his fellow judges during Startup Weekend LA, Healthcare.

Startup Competition Is Part of Cedars-Sinai Initiative to Accelerate Innovation

It was a weekend of hard work and sleepless nights that began with about 35 entrepreneurs and startup enthusiasts — most of whom had just met — brainstorming about ways to improve healthcare. It ended with applause and high fives as seven teams pitched new business models they had designed during an intense 54 hours, with the goal of making life better for patients around the world.

Between the beginning of the "Startup Weekend LA, Healthcare" event on Nov. 13 at a Cedars-Sinai facility and the final presentations on Nov. 15, individuals with very different skills and levels of experience took a deep dive into an intense, fast-paced process of transforming ideas into patient-centered healthcare solutions.

Omkar Kulkarni, MPH, Healthcare Innovation Accelerator director at Cedars-Sinai, helped organize the "idea competition" in collaboration with Techstars, a company that helps entrepreneurs around the world build successful businesses by providing support to accelerate the pace of innovation.

Among the participants were two Cedars-Sinai employees as well as a number of seasoned entrepreneurs and budding innovators. To enhance the educational value of the event, Kulkarni invited seven middle school students from the Incubator School in West Los Angeles, which provides early exposure to the experience of creating entrepreneurial ventures.

The students worked closely with the adults throughout the weekend. In fact, two 12-year-olds — along with Christina Yip, a data analyst in Cedars-Sinai Nursing Research and Development — were on the team that took first place.

The winning business models included a personalized patient education technology platform that earned the top prize — a chance to enter a video competition called the Global Startup Battle — as well as an online program to match licensed clinicians with healthcare facilities facing staff shortages and a one-stop online site that coordinates nonclinical services to help the elderly safely "age in place."

Bruce L. Gewertz, MD — surgeon-in-chief, chair of the Department of Surgery and the Harriet and Steven Nichols Distinguished Chair in Surgery — served on the judging panel along with Mandy Salzman, director at Techstars for Disney Accelerator, and Ash Kumra, Trade Kraft co-founder and CEO and a best-selling author. Gewertz is also vice president of Interventional Services and vice dean of Academic Affairs.

Throughout the weekend of brainstorming and business planning, mentors from Cedars-Sinai stopped by to share their healthcare expertise and offer business design guidance to the teams. Joseph Castongia, manager of Care Innovation and Design, said he was there to do for the startup teams what he does for Cedars-Sinai — help them "reimagine the way healthcare is delivered."

Castongia talked with the teams about the importance of understanding patients' emotions, attitudes and behaviors in order to come up with "human-centered" business models and solutions that will lead to a better healthcare experience as well as better health.

"It was interesting to see different types of people from the community come together to explore the possibilities of what the future of healthcare could look like — and to do so in a rapid-fire way that was really impressive," Castongia said. "The teams did an immense amount of work and came up with solid foundations for innovative products, services and solutions in just three days."

The weekend's activities are part of a broader Cedars-Sinai initiative to mentor entrepreneurial minds to drive breakthroughs in healthcare innovation. Cedars-Sinai recently announced a five-year partnership with Techstars to establish the Techstars Healthcare Accelerator in Partnership with Cedars-Sinai.

The three-month program, to be conducted annually, enables top healthcare technology entrepreneurs to grow their businesses with the help of funding and guidance provided by Cedars-Sinai leadership, clinicians and thought leaders, and by the Techstars network of more than 7,000 startup founders, mentors, investors and corporate partners. The accelerator program will accept 10-12 startup companies per class with pioneering ideas to improve the quality, safety and efficiency of health and healthcare delivery.

Gewertz, one of a number of Cedars-Sinai leaders who serve on the advisory board of the Techstars Healthcare Accelerator partnership, noted that Cedars-Sinai's commitment to mentoring creative minds — within the medical center and in the community — is vital to staying ahead of the curve. "Being generous with our expertise and nurturing talented entrepreneurs helps keep Cedars-Sinai at the cutting edge of innovation in healthcare," he said.


Startup Yip 480px

Christina Yip, a Cedars-Sinai data analyst, spoke for her team, which took first place in the competition.

Two Cedars-Sinai Employees Explore Startup World

Christina Yip, a data analyst in Nursing Research and Development, had to push herself to step up to the podium and talk about a healthcare business model she helped create during the three-day "Startup Weekend LA, Healthcare" event at Cedars-Sinai's Center for Clinical Innovation.

"I was nervous, but I thought this would be a really great opportunity to work on my public speaking skills," she said. "I'm really glad I spoke up."

"She did great," said Russ Dollinger, a Northridge entrepreneur who took an idea to the event that Yip and two other team members — Jordon Raeford and Emma Hanna, 12-year-olds from the Incubator School in West Los Angeles — helped develop during the three-day competition.

Startup Tran 220px
Michael Tran, a Performance Improvement facilitator at Cedars-Sinai, said the event motivated him to work on a business model for his idea.

Their concept for a business called MyNextGen Health won first place in the competition among seven teams. MyNextGen Health is a personalized patient education technology platform designed to overcome barriers to understanding pre- and post-operative instructions. Yip and her teammates will now have an opportunity to take their idea to the next level through a global video competition.

"I had the initial germ of the idea, but everyone contributed," Dollinger said. "The kids did some amazing things, including an online survey and the graphs for our presentation. And Christina was a very important part of the team. She worked hard on the nitty-gritty details. She was very focused."

Yip said this was her first startup experience. "I'm very interested in healthcare technology, and I wanted to understand the startup process from beginning to end," she said. "It was a great learning experience — and a lot of work. I definitely did not get my usual eight hours of sleep."

Michael Tran, a Performance Improvement facilitator at Cedars-Sinai, also played an important role as a team member in the competition.

Tran's team created a software platform called Reflect that empowers the elderly to live safely at home by making it possible for loved ones to track their daily activities from a distance. Tran said he contributed fall-detection advice to the platform that was inspired by concern for his own parents.

"I've always had ideas like this, but I'd talk myself out of pursuing them because I didn't have the technological know-how," he said. "This event put me in touch with people with different skill sets and motivated me to vet my idea and work on a business model. I learned a lot."

Cardiac Monitoring Policy Is Updated

In order to make beds with cardiac monitors available to more patients, Cedars-Sinai has adapted the 2004 American Heart Association cardiac monitoring guidelines for use as its policy concerning the utilization of cardiac monitoring of general medical-surgical adult inpatients.

Starting Nov. 7, when ordering cardiac monitoring for a patient, providers will select a diagnostic indication for cardiac monitoring. Based on this indication, cardiac monitoring will have an associated time limit, either 24 or 48 hours, or until the order is discontinued. Four hours prior to order expiration, physicians and bedside nurses will receive best practice alerts (BPAs) to evaluate the order for renewal.

Details about the change:

  • Providers will order cardiac monitoring by selecting the appropriate diagnostic indication for monitoring based on a table of indications.
  • Providers and nurses will receive a BPA four hours before the cardiac monitoring order expires.
  • Nurses can renew the cardiac monitoring order if the patient is clinically unstable or has a new or worsening arrhythmia. In addition, nurses will allow the cardiac monitoring orders to expire if the patient is clinically stable and free of any arrhythmias as per policy.
  • If a patient has discharge orders, or if a provider decides to let the cardiac monitoring order expire, neither providers nor nurses will continue to see the expiring order BPA.
  • Nurses will see a separate BPA if documentation shows that the patient is on cardiac monitoring without an active order. They will be prompted to contact a provider to obtain a cardiac monitoring order.

The cardiac monitoring change is one of several CS-Link™ updates that took effect Nov. 7. For more information and illustrations, see this document in CS-Link Central.

CS-Link Tip: Haiku Schedule Enhancement

If you look at your schedule on your phone, you will have noticed a change in Haiku. This enhancement allows you to see patients scheduled not only directly with you but also with other providers and resources as long as they are part of your multiprovider schedule.

If you do not choose a Default Schedule in Hyperspace, Haiku will function as it did previously. If you want to see something different, touch Schedule, then Options.

For more information and illustrations, see this document at CS-Link™ Central.

For CS-Link help, contact groupeisphysicians@cshs.org

Viorica Ionut, Research Scientist, 1968-2015

VioricaIonut_140pxViorica Ionut, MD, PhD, a research scientist in the Cedars-Sinai Diabetes and Obesity Research Institute and assistant professor of Biomedical Sciences, has died. She was 47. The cause was breast cancer.

An expert on the role of incretins, or gut hormones, in glucose homeostasis, Ionut came to Cedars-Sinai in 2011 from the University of Southern California. At USC, she worked in the laboratory of Richard Bergman, PhD, professor of Biomedical Sciences, who now directs the Cedars-Sinai Diabetes and Obesity Research Institute.

"Ionut was an integral part of our laboratory for a decade, both at USC and Cedars-Sinai," Bergman said. "She did important and ground-breaking work in the area of gut incretins. She investigated how the intestinal tract communicates with other organs, how this communication is impaired in diabetes and obesity, and how we can use this information to develop better therapeutic strategies."

Among Ionut's contributions was to identify the porto-hepatic area — where vessels enter or leave the liver — as a new locus for sensing metabolic and hormonal information from the intestine. She established the importance of this region in controlling blood glucose levels, independent of pancreatic hormones. Her research had significant implications for treatment of Type 2 and Type 1 diabetes.

Bergman noted that incretin hormones have been widely used in various medicines for diabetes. "Ionut deserves much credit for helping us understand how these hormones work so that these medicines can be used in patients," he said.

Inout was born in Cluj-Napoca, Romania, and obtained her MD from the University of Medicine and Pharmacy in that city. After residency, she moved to Rutgers University, where she studied Nutrition Science. At USC, she obtained her PhD in Physiology and attained the rank of assistant professor. At Cedars-Sinai, she was accepted into the Clinical Scholars Program, which trains clinicians to become clinical scientists, in 2011 and graduated in September of this year.

Bergman remembered Ionut as a "great scholar, educated and insightful." He added: "She had a wonderful personality. She was warm and giving, and had an outstanding sense of humor. This is a great loss for Cedars-Sinai."

Ionut is survived by her husband, Clay, and a son, Ricky.

Open Enrollment for Individual/Family Plans Runs Through Jan. 31

From Thomas M. Priselac, President and CEO

We are about to embark on the third annual open enrollment period for individual and family health insurance plans since the Affordable Care Act was signed into law.

This does not impact those of you who are covered by Cedars-Sinai-sponsored health insurance plans through Anthem Blue Cross. If you receive questions from patients — or if you have friends or family members who purchase individual and family health insurance plan on their own — you can advise them that only certain plans cover care from Cedars-Sinai.

Open enrollment for individual and family health insurance runs through Jan. 31, 2016. During this time, people can enroll in coverage or change their plan. Please note that this open enrollment only affects people who purchase their own insurance policies for themselves and their families.

The following plans now provide coverage for care from Cedars-Sinai:

  • Through the Covered California health benefit exchange:
    • Anthem Blue Cross PPO plans
      • All metal levels — e.g., Platinum, Gold, Silver, Bronze
      • Those who belonged to an Anthem Blue Cross EPO plan in 2015 will automatically have their plan change to the PPO plan for 2016.
    • Blue Shield of California PPO plans
      • All metal levels — e.g., Platinum, Gold, Silver, Bronze
  • Through an insurance broker or insurance company directly (off the exchange):
    • Anthem Blue Cross PPO
      • All metal levels — e.g., Platinum, Gold, Silver, Bronze
      • Those who belonged to an Anthem Blue Cross EPO plan in 2015 will automatically have their plan change to the PPO plan for 2016.
    • Blue Shield of California PPO
      • All metal levels — e.g., Platinum, Gold, Silver, Bronze

Two insurers that previously provided plans that included coverage for Cedars-Sinai Medical Center have changed their offerings for the 2016 plan year. Patients enrolled in plans from these insurers will need to select a new plan by Dec. 15, 2015, to avoid a lapse in coverage.

  • Assurant Health has discontinued offering individual and family health insurance coverage and will not participate in this open enrollment period.
  • Health Net has discontinued offering the individual and family PPO plans that previously covered care from Cedars-Sinai Medical Center.

We recognize there are many people who want to come to Cedars-Sinai, but may be concerned about out-of-pocket costs such as deductibles and co-pays for hospital services. To make things easier for our patients, we offer a variety of financial assistance programs that can help people with some of these costs. These programs are available to a wide range of incomes, and more information is available online or by calling Patient Financial Services at 323-866-8600.

For the most up-to-date information and guidance, please access the following resources:

Study Sheds Light on 'Superbug' Treatment

A new study sheds light on how treatment of the "superbug" known as MRSA with certain antibiotics can potentially make patients sicker. The findings by Cedars-Sinai scientists, published Nov. 11 in the journal Cell Host & Microbe, could have implications for managing the bug, a virulent form of the common staph infection that can be difficult to control.

MRSA, or methicillin-resistant Staphylococcus aureus, recently made the news when New York Giants tight end Daniel Fells received treatment for it. MRSA has long caused problems in the sports world, especially in football and wrestling, in which athletes have close body contact. But anyone can contract the infection when the bacteria enter the body through a cut, sore, catheter or other means.

MRSA causes more than 80,000 invasive infections and 11,000 related deaths per year, according to 2011 figures from the federal Centers for Disease Control and Prevention. Fatalities are more likely when the bacteria enter the bloodstream or lungs, according to George Liu, MD, PhD, co-senior author of the Cell Host & Microbe article. "It is one of the biggest antibiotic-resistant pathogens in the U.S.," said Liu, a pediatric infectious diseases physician at Cedars-Sinai's Maxine Dunitz Children's Health Center and the F. Widjaja Inflammatory Bowel and Immunobiology Research Institute.

The research team cautioned that their findings were based on laboratory studies of mice and that the results need to be carefully evaluated in human subjects for validation.

"Based on this research, clinical studies are warranted," said study author Sabrina Mueller, PhD. "However, pending the outcome of those studies, physicians should follow current national guidelines set by the Infectious Diseases Society of America for antimicrobial treatment of staph infections."

Although many studies have established that MRSA infections cause more severe diseases compared with normal staph infections, what makes MRSA so pathogenic is not entirely clear. The Cedars-Sinai scientists found one answer in the name of the superbug — methicillin-resistant. In laboratory mice, treatment with antibiotics similar to methicillin, called beta lactams, caused the MRSA bacteria to build cell walls that are highly inflammatory and damaging to tissues.

The scientists explained that beta-lactam antibiotics kill normal staph bacteria by inactivating their cell-wall-making enzymes. But one of these enzymes, PBP2A, which is induced when MRSA is exposed to beta-lactam antibiotics, is not rendered inactive by the antibiotics. In fact, PBP2A allows the superbug to continue making its cell wall. Further, the cell wall's structure differs from that of normal staph, and not in a good way.

"This altered cell wall induces a powerful inflammatory response," said the study's co-senior author, David Underhill, PhD, associate director of the Division of Immunology Research in the Cedars-Sinai Department of Biomedical Sciences and the Janet and William Wetsman Family Chair in Inflammatory Bowel Disease. "In mice infected with MRSA, induction of PBP2A with methicillin led to more inflammation and pathology."

In other words, the mice became sicker.

The authors said their study findings in mice raised the possibility that prescribing beta-lactam antibiotics to treat infections in humans may worsen the infection, should the source prove to be MRSA. The potential dilemma for physicians is that beta-lactam antibiotics' overall effectiveness often makes them the first line of defense when the origin of a severe infection is unknown. And it can take a day or two to culture MRSA, making early diagnosis difficult, Liu said.

"There is much work ahead of us before we can make a firm recommendation about the advantages or disadvantages of treatment with beta-lactam antibiotics," Liu said.

The study was supported by the National Institutes of Health under award numbers R21AI097741, R01GM085796 and DK098310.