Antimicrobial ResistanceTravis Neill, PA-C

Assistant to the Medical Director

Financial Disclosures

Life Before Antibiotics and Vaccines● An estimated 2 to 6 million military personnel died from infections in

WWI, including a bacterial infection causing tetanus- an agonizing slow death of increasing paralysis culminating in lock-jaw

● Tuberculosis, Syphilis, Pneumonia, Whooping Cough, all caused by aggressive bacteria that reproduced with extraordinary speed and led to serious illness and often death

Life Before Antibiotics and Vaccines

● Surgery mortality rates were approx 70% higher before antibiotics

● Maternal Mortality Rates were approx 60% higher before antibiotics

● Before antibiotics, 90% of children with bacterial meningitis died. Among those children who lived, most had severe and lasting disabilities, from deafness to mental retardation

● Strep throat was at times a fatal disease, and ear infections sometimes spread from the ear to the brain

● Simple cuts or puncture wounds could often be fatal, removing limbs due to infection was common “the saw”

History of Antibiotics

● Alexander Fleming - Penicillin initially discovered in 1928 but was not used for treating bacterial infections on a large scale until 1944

● Fleming also discovered very early that bacteria developed antibiotic resistance whenever too little penicillin was used or when it was used for too short a period.

● Fleming: “The microbes are educated to resist penicillin and a host of penicillin-fast organisms is bred out ... In such cases the thoughtless person playing with penicillin is morally responsible for the death of the man who finally succumbs to infection with the penicillin-resistant organism. I hope this evil can be averted."

● He cautioned not to use penicillin unless there was a properly diagnosed reason for it to be used, and that if it were used, never to use too little, or for too short a period, since these are the circumstances under which bacterial resistance to antibiotics develops.

*Also the first Antibiotic Stewardship champion!!

The 1950s - A Golden Era for Antibiotics

● The triumph of Penicillin streamlined the production of dozens of new antibiotics during the 1950s, in fact half of the drugs in use today were discovered during this decade

● Antibiotics are omnipresent in nature but never before have humans been exposed to mass production and use of antibiotics

● By 1953 the US was spending $100 million a year on antibiotics

Without effective antimicrobials for prevention and treatment of infections, medical procedures such as organ transplantation, cancer

chemotherapy, diabetes management and major surgery (for example, caesarean sections or hip replacements) become very high risk.

By the 1960s leading scientists and doctors declared the fight against infections won and we saw a shift toward more lucrative

drugs to fight cancer and heart disease.

Toxic Side Effects of Antibiotics

● During the same golden era, we simultaneously began to see a rise in certain diseases and deaths thought to be caused by the antibiotics.

○ Gray baby syndrome is a serious side effect that occurs in newborn infants following the accumulation of antibiotic chloramphenicol.

○ Pseudomembranous colitis became a commonly recognized complication of antibiotic use in the early 1950s and was primarily encountered by surgeons, who reported rates as high as 14%–27% among postoperative patients

● By the end of the 1950s the toxic side effects of antibiotics were well known and we saw a dramatic increase in antibiotic resistant infections

The Golden Era of “C. difficile”Following the Golden Era of antibiotics was the “C. difficile era” which began in 1974, when Tedesco et al. reported high rates of PMC among patients at Barnes Hospital (St. Louis, MO) who were receiving clindamycin. This study was the first in which endoscopy was a routine diagnostic procedure for patients with antibiotic-associated diarrhea. Of 200 patients given clindamycin, diarrhea developed in 42 (21%). Twenty clindamycin recipients (10%) had PMC at the time of endoscopy.

In 2017 an estimated 250,000 illnesses and 14,000 deaths

occurred from C. difficile related infections

Toxic Side Effects of Antibiotics

CDC. Threat Report 2013. http://www.cdc.gov/drugresistance/threat-report-2013/

Toxic Side Effects of Antibiotics

The “Gut Microbiome” aka the human gastrointestinal tract

● The bacterial cells harbored within the human gastrointestinal tract (GIT) outnumber the host’s cells by a factor of 10 and the genes encoded by the bacteria resident within the GIT outnumber their host’s genes by more than 100 times.

● The gut microbiota in humans evolve throughout life and appear to play a pivotal role in both health and disease.

● A dysbiotic state of the gut microbiota is becoming recognized as an environmental factor that interacts with a host’s metabolism and has a role in pathological conditions, both systemic—obesity, diabetes, and atopy—and gut-related IBS and IBD.

Toxic Side Effects of Antibiotics

The “Gut Microbiome” aka the human gastrointestinal tract

● Fecal transplant pills (crapsules) - in 2013 a study in the NEJM on C.diff was stopped early due to faecal microbiota transplant (FMT) being so effective it was ruled unethical to withhold it from other participants in the study.

● A trial published in The Lancet in early 2017, found that FMT led to complete remission in just over one in four patients with ulcerative colitis. And a study in JAMA, in November 2017 found that for C. difficile, in which FMT is up to 90% effective, crapsules worked just as well as FMT via colonoscopy.

Are we human or microbes?

● Human cells make up only 43% of the body's total cell count. The rest are microscopic colonists. You are more microbe than you are human.

● We are simply one of many host platforms for microorganisms to wage warfare.

● As these genetically coded bacteria get attacked by antibiotics they selectively code for traits that allow them to survive.

● Most antimicrobial compounds are naturally-produced molecules, and, as such, co-resident bacteria have evolved mechanisms to overcome their action in order to survive “intrinsic resistance”

Antibiotic Resistance - Superbugs

● Superbugs are microorganisms that have developed resistance to one or more, or all antibiotics.

● In many ways, they are worse than cancer. Many cancers can now be cured, but not infection by a superbug that is resistant to all antibiotics. Cancer doesn’t spread to another person but a superbug infection can spread like wildfire. There are now many infections that cannot be treated at all.

● The problem with our rampant use of antibiotics is the development of “acquired resistance” in a bacterial population that was originally susceptible to the antimicrobial compound.

A particularly ingenious weapon in the bacterial arsenal is the drug efflux pump. These pumps are proteins located in the membranes of bacteria that can recognize and expel drugs that have breached the membranes. In some cases, the bacterial pumps have become so advanced they can recognize and expel drugs with completely different structures and mechanisms so it can act on multiple antibiotics. A bacterium can go from being drug-susceptible to resistant to five or six different drugs by acquiring a single gene.”

Efflux Pumps - Acquired Resistance

Antibiotic Resistance - Superbugs

More than 2 million people are infected by Superbugs each year, and 23,000 die of their infections (recent CDC data)

Many of the most urgent and serious antibiotic-resistant bacteria threaten patients while they are being treated in healthcare facilities for other conditions, and may lead to sepsis or death. In acute care hospitals, 1 in 7 catheter- and surgery-related HAIs can be caused antibiotic-resistant bacteria. That number increases to 1 in 4 infections in long-term acute care hospitals, which treat patients who are generally very sick and stay, on average, more than 25 days.

Antibiotic Resistance - Superbugs

Current CDC Data

● Carbapenem-resistant Enterobacteriaceae (CRE) - Drug-resistant infections per year: 9,000, Deaths per year: 600

● Methicillin-resistant Staphylococcus aureus (MRSA) - Severe MRSA infections per year: 80,461, Deaths per year: 11,285

● ESBL-producing Enterobacteriaceae (extended-spectrum β-lactamases) - Drug-resistant infections per year: 26,000

● Vancomycin-resistant Enterococcus (VRE) - Drug-resistant Enterococcus infections per year: 20,000, Deaths per year: 1,300

● Multidrug-resistant Pseudomonas aeruginosa - Multidrug-resistant Pseudomonas infections per year: 6,700, Deaths per year: 440

● Drug-resistant Neisseria gonorrhoeae - Infections per year: 246,000

● Drug-resistant Campylobacter - Drug-resistance infections per year: 310,000

Antibiotic Resistance - Superbugs

The World Health Organization has named antibiotic resistance as one of the three most important public health threats of the

21st century

Antibiotic Resistance - Superbugs

● Resistance in Klebsiella pneumoniae – common intestinal bacteria that can cause life-threatening infections – to a last resort treatment (carbapenem antibiotics) has spread to all regions of the world. K. pneumoniae is a major cause of hospital-acquired infections such as pneumonia, bloodstream infections, and infections in newborns and intensive-care unit patients. In some countries, because of resistance, carbapenem antibiotics do not work in more than half of people treated for K. pneumoniae infections.

● Treatment failure to the last resort of medicine for gonorrhoea (third generation cephalosporin antibiotics) has been confirmed in at least 10 countries (Australia, Austria, Canada, France, Japan, Norway, Slovenia, South Africa, Sweden and the United Kingdom of Great Britain and Northern Ireland).

● Increasingly, E. coli is proving resistant not just to individual antibiotics, but also to a broad group of drugs known as beta-lactam antibiotics. These drugs share a way of attacking infection, and when a germ develops resistance to this method of attack, it eliminates several key treatment options all at once.

● The New York City Department of Health’s research found that a third of uncomplicated urinary tract infections caused by E. coli were now resistant to Bactrim, one of the most widely used drugs, and at least 20% of them were resistant to five other common treatments.

● Researchers last year reported in a study that 30% of all UTIs in Britain are resistant to “key antibiotics.”

Antibiotic Resistance - Superbugs● Resistance to first-line drugs to treat infections caused by

Staphlylococcus aureus is widespread. People with MRSA (methicillin-resistant Staphylococcus aureus) are estimated to be 64% more likely to die than people with a non-resistant form of the infection.

● Colistin is the last resort treatment for life-threatening infections caused by Enterobacteriaceae which are resistant to carbapenems. Resistance to colistin has recently been detected in several countries and regions, making infections caused by such bacteria untreatable.

● Patients with Carbapenem Resistant Enterobacteriaceae (CRE) infections have few treatment options and face high levels of mortality. Carbapenems aren't the only problem either; there are emerging infections susceptible to few — and sometimes no — available antibiotics. A strain of Klebsiella pneumoniae resistant to all antibiotics emerged in the U.S. in 2016.

A Post-Antibiotic Era

Currently:

● 80% of gonorrhoeal infections are now resistant to antibiotics.

● 440,000 new cases of drug-resistant tuberculosis annually.

In the not too distant future:

● Strep throat to a scraped knee could kill you.

● A simple hip replacement would result in 1 and 6 deaths.

● The cost to treat drug-resistant cases is estimated to be at least double.

A Historic Miscalculation

● The FDA drug approval process has become increasingly more robust making it more expensive to bring a drug to market

● Antibiotic R&D slowed in the 1960s while prominent scientists around the world declared victory over infectious diseases

● The medical industrial complex evolves to focus more on profit and high income producing drugs for chronic diseases (statins, opioids, insulin)

● Bacteria evolve to grow more resistance mechanisms (efflux pumps, enzymatic inactivation, decreased cell permeability)

● Tremendous advances occur in science during the 1970s and 1980s like gene splicing and sequencing but no new classes of antibiotics are introduced during these decades.

● As we wipe out both good and bad bacteria, we are seeing a giant rise in diseases thought to be linked to our altered microbiome: inflammatory bowel disease, obesity, diabetes, and atopy.

● Estimated 34,000 deaths per year from superbugs

Antibiotics Lack Profit Incentive● The net present value to bring an antibiotic to market is negative -$50 million according to the London School of Economics

● They are used judiciously, over short periods of time and resistance WILL develop within 5 years

● Currently costs over $1B and 10yrs of testing to bring a new drug to market

● Antibiotics have the highest failure rate among all new drugs

● Clinical trials for antibiotics are more complex and costly

The Genomic Sequencing Of H. Influenzae

● A landmark study in 1995 published the entire genomic sequence of the bacterium Haemophilus influenzae

● This led to a spike in investment from Big Pharma like GlaxoSmithKline(GSK) over the prospect of developing new drugs to target hundreds of genes

● Nearly 500,000 compounds were screened by GSK scientists from 1995 to 2001 but not a single one was useful in humans

● This proved to be a giant failure and waste of money which caused GSK and other companies to be even more conservative about investing into antibiotics - a monumental setback to antibiotic development

Achaogen Bankruptcy

● Founded in 2002, it is an antibiotic development company

● Its first drug, Zemdri (plazomicin), was approved by the FDA in June 2018

● Achaogen hit all the marks that should have signaled success. It recruited experienced developers, targeted an infection that the World Health Organization considers a critical unmet need, stuck with its compound through 15 years of testing, scored several rounds of public investment and private philanthropy, and got its drug approved.

● They were banking on approval for bacteremia but only gained approval for treatment of UTIs and there were already better cheaper options

● Filed for bankruptcy in April 2019

● Over 90% of the antibacterial products in development today are from small companies, and over 60% of these companies have no other products on the market while big pharma companies like Novartis, AstraZeneca and Sanofi are closing their antibiotic R&D programs

Options for Incentivizing New Antibiotics

● Push Incentives - Push incentives provide support for research and development, but they don't ensure that a company can get an adequate return on a new antibiotic once it wins approval

● Pull Incentives - Pull incentives can be designed so that the rewards to companies are not based solely on sales volume, thus reducing the incentive to maximize sales of a drug while under patent, the report says. To promote access to the drug, payments can be made in stages as the sponsor meets conditions for responsible marketing, product registration, and/or pricing. Other mechanisms for promoting access include using patent buyouts or licensing mechanisms to give public bodies or other groups control over manufacturing and distribution of the drug in "key territories."

● Subscription type service for hospitals

In Summary

● Antibiotic Stewardship is part of the solution to one of the biggest problems facing our species - antibiotic resistant superbugs

● Please educate yourself and advocate for more incentives for antibiotic development - reach out to policymakers

● Antibiotic Stewardship also reduces the risk of diseases caused by antibiotics as the evidence that changes in our gut microbiome continues to show strong correlations with more diseases

● Antibiotic Use in Nursing Homes is estimated to be inappropriate on average about 50% of the time

● Remember that 20% of providers account for 80% of the antibiotic prescriptions

Antimicrobial Stewardship Resourceshttp://www.health.state.mn.us/divs/idepc/dtopics/antibioticresistance/ltcabxcard.htmlMinimum Criteria for Initiation of Antibiotics in Long-Term Care Residents

http://www.rochesterpatientsafety.com/index.cfm?Page=For%20Nursing%20HomesRochester Nursing Home collaborative, lots of good information on Abx Stewardship

https://www.cdc.gov/drugresistance/solutions-initiative/antibiotic-stewardship.htmlCDC antibiotic stewardship resources

Thank You!