National Center for Emerging and Zoonotic Infectious Diseases

Antibiotic Resistance in the United States

Alex Kallen, MD, MPH, FACP, FIDSA, FSHEA

January 21, 2020

Questions

Why is it important to do this?

– Why containing antibiotic resistance is important?

– What is special about Acinetobacter?

How is the approach to controlling resistance within a region changing?

SECTION 1 The Threat Of Antibiotic Resistance

The Threat of Antibiotic Resistance in the United States

The New National Estimate states that:

– Each year, antibiotic-resistant bacteria and fungi cause at least an estimated 2 million 868 thousand 700 infections. And 35 thousand 900 deaths.

The national burden reflects de-duplicated infection and death estimates.

– Clostridioides difficile is related to antibiotic use and antibiotic resistance. It caused 223 thousand 900 cases and 12 thousand 800 deaths in 2017.

The New Antibiotic Resistance Threats List includes:

– Updated urgent, serious, and concerning threats, totaling 18 threats.

– 5 urgent threats, 2 new threats, and a new watch list with 3 threats.

Antibiotic resistance remains a significant One Health problem, affecting humans, animals, and the environment. Data show infection prevention and control is saving lives, especially in hospitals, but threats may undermine this progress without continued aggressive action now.

Learn more at w w w dot c d c dot gov slash Drug Resistance slash Biggest hyphen Threats. Drug Resistance is one word.

Antibiotic-Resistant Infections Threaten Modern Medicine Full Version Antibiotic-Resistant Infections Threaten Modern Medicine Antibiotic-Resistant Infections Threaten Modern Medicine.

Millions of people in the United States receive care that can be complicated by bacterial and fungal infections. Without antibiotics, we are not able to safely offer some life-saving medical advances.

– One: Sepsis Treatment.

• Anyone can get an infection and almost any infection can lead to sepsis—the body’s extreme response to an infection. Without timely treatment with antibiotics, sepsis can rapidly lead to tissue damage, organ failure, and death.

• At least 1 point 7 million adults develop sepsis each year.

– Two: Surgery.

• Patients who have surgery are at risk for surgical site infections. Without effective antibiotics to prevent and treat surgical infections, many surgeries would not be possible today.

• At least 1 point 2 million women had a C-section in 2017. Antibiotics are recommended to help prevent infection.

– Three: Chronic Conditions.

• Chronic conditions such as diabetes put people at higher risk for infection. These conditions and some medicines used to treat them can weaken the immune system and how the body fights infection.

• More than 30 million people have diabetes. Antibiotics are used to treat common infections in these patients.

Page 2: Antibiotic-Resistant Infections Threaten Modern Medicine Full version Millions of people in the United States receive care that can be complicated by bacterial and fungal infections. Without

antibiotics, we are not able to safely offer some life-saving medical advances.

The image highlights three ways antibiotics help with medical advances:

– One: Organ Transplants.

• Organ transplant recipients are more vulnerable to infections because they undergo complex surgery. Recipients also receive medicine to suppress, or weaken, the immune system, increasing risk of infection.

• More than 33 thousand organ transplants were performed in 2016. Antibiotics help organ transplants remain possible.

– Two: Dialysis for Advanced Kidney Disease.

• Patients who receive dialysis treatment have a higher risk of infection, the second leading cause of death in dialysis patients.

• More than 500 thousand patients received dialysis treatment in 2016. Antibiotics are critical to treat infections in patients receiving life-saving dialysis treatment.

– Three: Cancer Care.

• People receiving chemotherapy for cancer are often at risk for developing an infection during treatments. Infection can quickly become serious for these patients.

• Around 650 thousand people receive outpatient chemotherapy each year. Antibiotics are necessary to protect these patients.

We Can’t Rely on Antibiotics Alone to Fix this Problem As a result of difficult scientific obstacles and challenging business incentives, many pharmaceutical companies are getting out of the antibiotic business altogether.

Between 1962 and

2000, no new major classes

of antibiotics were approved to treat

common and deadly Gram-negative

infections.6

Since 1990, 78% of major drug

companies

have scaled back or cut antibiotic research due to

development challenges. 7

Historical data show that, generally, only

1 out of 5 infectious disease drugs that

reach the initial phase of testing in humans will receive approval

from the FDA. 8

Germs Fight Back: Resistance Mechanisms

To survive the effects of antibiotics, germs are constantly finding new defense strategies, called “resistance mechanisms”

These mechanisms can change over time and lead to more resistant infections

Alarmingly, some antibiotic-resistant germs can share their resistance genes with other germs that have not been exposed to antibiotics

Some resistance mechanisms might be more concerning than others

How Bacteria and Fungi Fight Back against Antibiotics

Antibiotics fight germs such as bacteria and fungi. But germs fight back and find new ways to survive. Their defense strategies are called resistance mechanisms.

– One. Germs develop new cell processes that avoid using the antibiotic’s target.

– Two. Germs change or destroy the antibiotics with enzymes, proteins that break down the drug.

– Three. Germs restrict access by changing the entryways or limiting the number of entryways.

– Four. Germs change the antibiotic’s target so the drug can no longer fit and do its job.

– Five. Germs get rid of antibiotics using pumps.

Only germs, not people, become resistant to antibiotics.

How Antibiotic Resistance Moves Directly Germ to Germ

Any antibiotic use can lead to antibiotic resistance. Antibiotics kill germs like bacteria and fungi, but the resistant survivors remain. Resistance traits can be inherited generation to generation. They can also pass directly from germ to germ by way of mobile genetic elements.

The image describes three mobile genetic elements. These are plasmids, transposons, and phages.

– Plasmids are circles of DNA that can move between cells.

– Transposons are viruses that attack germs and can carry DNA from germ to germ.

– Phages are small pieces of DNA that can go into and change the overall DNA of a cell. Phages can move from chromosomes, which carry all the genes essential for germ survival, to plasmids and back.

The image then describes how mobile genetic elements work through transduction, conjugation, and transformation.

– Transduction is when resistance genes can be transferred from one germ to another via phages.

– Conjugation is when Resistance genes can be transferred between germs when they connect.

– Transformation is when resistance genes released from nearby live or dead germs can be picked up directly by another germ.

Isolate collected in 1996 during an ICU surveillance project from NC

The US Carbapenemase: KPC

Geographical of KPC-producing CRE, 2001-2017

Division of Healthcare Quality Promotion

DC* DC* DC* DC*

DC* DC* DC* DC*

States with Klebsiella pneumoniae carbapenemase (KPC)-producing Carbapenem-resistant Enterobacteriaceae (CRE) confirmed by CDC

KPC-CRE found in the US spread from 2 states in 2001 to 49 states, DC, and PR in 16 years

2001

2010

2005

2012

2006

2014

2008

2017

Important Antibiotics Can Quickly Lose Efficacy

Friedman N, et. al. (2017). doi:10.1017/ice.2017.42

SECTION 2 Approach to Controlling Emerging Antibiotic-Resistant

Infections

CLOSTRIDIOIDES DIFFICILE

The Fight Against Antibiotic Resistance

The image is laid out like a timeline, starting in 2013 and ending in 2019.

In 2013, C D C releases the Antibiotic Resistance Threats in the United States, 2013.

In 2014:

– CDC publishes Core Elements of Hospital Antibiotic Stewardship Programs. Other settings followed.

– White House Executive Order 1 3 6 7 6 establishes National Strategy for Combating Antibiotic-Resistant Bacteria and Presidential Advisory Council.

In 2015:

– U S government releases National Action Plan for Combating Antibiotic-Resistant Bacteria.

– Congress appropriates 160 million dollars for C D C’s A R Solutions Initiative, as part of funding across the U S government to implement National Action Plan for Combating Antibiotic-Resistant Bacteria. C D C’s initial request was 264 Million dollars.

– C D C launches C D C and F D A Antibiotic Resistance Isolate Bank.

In 2016:

– C D C establishes A R Lab Network and funds local A R experts in every state, some major cities, and Puerto Rico.

– C D C awards first innovation funding of 40 million dollars to academic, industry, and healthcare investigators, including C D C’s Prevention Epicenters Program.

– C D C launches the Antibiotic Use and Antibiotic Resistance tracking modules through the National Healthcare Safety Network.

– United Nations General Assembly holds high-level meeting on A R.

In 2017:

– C D C begins supporting innovation to combat A R globally.

– C D C adds National Tuberculosis Molecular Surveillance Center to AR Lab Network.

– Food and Drug Administration releases Veterinary Feed Directive to help ensure antibiotics only used to treat and prevent infections in food animals.

CDC’s AR Lab Network

Transform the national lab infrastructure with regional and local labs with gold-standard methods and technology

Enhanced testing capacity in all 50 states, four local jurisdictions, and Puerto Rico

Faster detection for rapid and improved public health response

Communication channels to engage clinical laboratory partners

Real-time, actionable data to combat AR threats

Health Departments Are Combating Antibiotic Resistance The image shows 3 ways Health Departments are combating A R. Followed by 3 ways they need help to continue the fight.

– The first: Lab Data are Enhancing Local Response by Rapidly detecting A R through C D C’s Antibiotic Resistance Laboratory Network, and Informing local responses to prevent spread.

• However, Gaps in Lab Capacity can Allow Germs to Spread Undetected. For example, New types of resistance are constantly emerging and spreading. Labs need specialized workforce to implement and use new technologies.

– The second: Prevention & Containment are Stopping Spread by supporting aggressive responses to all unusual resistance. Also working with local partners and healthcare facilities to track and prevent healthcare-associated, foodborne, and community infections caused by antibiotic-resistant germs.

• However, More Boots on the Ground are Needed to Stop Transmission. More infection control responses are needed as new threats emerge in healthcare and the community. Poor access to the best data tools can hurt efforts to learn about resistant germs and affected people. Containment responses can be labor intensive and lab-epidemiology coordination is essential to stop the spread of new threats

– The third: Improving Antibiotic Use Slows Development of A R by using data to improve antibiotic use and keeping antibiotics effective for life-threatening infections, including those that can lead to sepsis. Also leading or supporting improvements to antibiotic use in humans, animals, and the environment.

• However, Changing Prescribing Habits & Expectations Require Investment. Improving antibiotic use across settings such as healthcare, farms, the environment is complex and needs tailored interventions. Tracking antibiotic use in settings like nursing homes and long-term care facilities often does not exist or is difficult.

Patient Movement Between Healthcare Facilities: Public Health Intervention is Critical

Modeling of patient movement between different healthcare settings (acute care, long-term care, etc.) in Washington

(squares) and Oregon (circles): Targeting highly connected facilities is key.

Slayton et al., submitted for peer review

Outbreak stemming from a single case of CRE across 4 adjacent counties in Indiana and Illinois.

Won SY et al., Emergence and rapid regional spread of Klebsiella pneumonia

carbapenemase-producing Enterobacteriaceae. Clin Infect Dis 2011 53(6):532-40.

Containment Strategy Systematic public health response to slow the spread of emerging AR

Single case of emerging resistance: Pan-R, carbapenemase-producing organisms, Candida auris

Available through ARLN Onsite assessment using standardized tools

Regular infection control assessments and point

prevalence surveys until transmission stops

DETECTION INFECTION CONTROL CONTACT SCREENING

Potential Impact of Containment Strategy

Prabasaj Paul, Rachel B Slayton, Alexander J Kallen, Maroya S Walters, John A Jernigan, Modeling Regional Transmission and Containment of a Healthcare-associated Multidrug-resistant Organism, Clinical Infectious Diseases, ciz248, https://doi.org/10.1093/cid/ciz248

What Comes Next – Regional Strategies for Controlling High Concern Resistance

Application of Interventions in a National Setting Israel KPC-CRE Outbreak

Schwaber et al, CID 2011; 52: 848-55

Inclusion of LTCF Active surveillance

Application of Interventions in a National Setting Israel KPC-CRE Outbreak

Interventions -Infection Control education -Active surveillance -Gowns and gloves -Resident cohorting

Ben-David et al, CID 2018

Infection Prevention in Hospitals is Working

CDC's 2019 AR Threats Report: Prevention works.

18% fewer deaths from antibiotic resistance overall since 2013 report.

28% fewer deaths from antibiotic resistance in hospitals since 2013 report.

And decreases in infections caused by:

Vancomycin-resistant Enterococcus, a 41% decrease; Multidrug-resistant pseudomonas aeruginosa, a 29% decrease; Methiciliin-resistant Staphylococcus aureus (MRSA), a 21% decrease; Carbapenem-resistant Acinetobacter, a 33% decrease; Drug-resistant Candida, a 25% decrease; Carbapenem-resistant Enterobacteriaceae (CRE) & drug-resistant tuberculosis (TB disease cases) are stable.

SECTION 3 Pathogen Summary

Current Antibiotic Resistance Threats in the U.S.

Urgent Threats Carbapenem-resistant

Acinetobacter

Candida auris

C. difficile

Carbapenem-resistant Enterobacteriaceae

Drug-resistant Neisseria gonorrhoeae (N. gonorrhoeae)

Serious Threats Drug-resistant Campylobacter

Drug-resistant Candida

ESBL-producing Enterobacteriaceae

Vancomycin-resistant Enterococci

Multidrug-resistant Pseudomonas aeruginosa

Drug-resistant nontyphoidal Salmonella

Drug-resistant Salmonella serotype Typhi

Drug-resistant Shigella

Methicillin-resistant Staphylococcus aureus

Drug-resistant Streptococcus pneumoniae

Drug-resistant Tuberculosis

Concerning Threats Erythromycin-resistant Group A

Streptococcus

Clindamycin-resistant Group B Streptococcus

https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf

Carbapenem-Resistant Acinetobacter baumannii

https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf

Incidence of CRAB Cases by Year, from EIP Surveillance, 2012-2018, n=984

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Epidemiologic Class of CRAB Cases Identified Through EIP Surveillance, 2012-2015, N=598

Healthcare Associated

Community Associated

88% had inpatient healthcare exposure in prior year

– 78% admitted to ACH

– 60% resided in LTC

– 33% underwent surgery

– 14% admitted to LTACH

Bulens SN, Yi SH, Walters MS, Jacob JT, Bower C, Reno J, et al. Carbapenem-Nonsusceptible Acinetobacter baumannii, 8 US Metropolitan Areas, 2012–2015. Emerg Infect Dis. 2018;24(4):727-734. https://dx.doi.org/10.3201/eid2404.171461

CP- A. baumannii Can Contaminate the Patient Care Environment and Shared Medical Equipment

• 106 CRAB from 15 states, 2013-20152 • 77 isolates from 8 sentinel surveillance sites • 29 isolates from reference testing

Carbapenemases are Frequent Cause of Carbapenem Resistance in CRAB

Courtesy of Dr. Maria Karlsson, CDC

OXA-subgroup N %

OXA-23 53 50%

OXA-24/40-like 20 18%

OXA-235-like 7 7%

Acquired OXA-variants identified among 106 CRAB

62% were ST-2

Carbapenemase-Producing CRAB Outbreaks Reported to CDC, 2017-2019, By Mechanism and Type, N=33

CDC, Data are Preliminary and Subject to Change

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Single Facility clusters (n=12)

Multi-site clusters (n=10)

Outcomes Associated with CRAB Cases, EIP Surveillance, 2012-2017, N=863

18% died during hospitalization or ≤30 days after culture collection

41% of cases from sterile sites

8% of cases from urine

75% hospitalized at time of or ≤30 days after culture collection

37% admitted to ICU

Limited Antibiotic suscpetibilites

Bulens at al. EID April 2018

New Drugs available for treating CRAB

Cefiderocol

6 other agents in Phase 1 with clear activity against Acinetobacter – all represent previously used classes:

– Two tetracyclines

– Sulbactam + BLI

– Quinolone

– Polymixin

– Cefepime+BLI

Antibacterial Agents in Development WHO 2017 PEW charitable Trust Sept 2019 Antibiotics Currently in Global Clinical development

For more information, contact CDC 1-800-CDC-INFO (232-4636) TTY: 1-888-232-6348 www.cdc.gov The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.