Antibiotic steward
2015 MSIPC Annual Fall Conference
Crowne Plaza Lansing Michigan
October 8-9 2015
Anthony F Ognjan, DO FACP
*Promoting Antimicrobial Stewardship in Human Medicine Infectious Disease Society of America
http://www.idsociety.org/Stewardship_Policy/#sthash.7G8b9Xis.dpufhttp://www.idsociety.org/Stewardship_Policy/ (Accessed 7/7/2015)
Anthony Ognjan,D.O., FACP
(Hungarian - French Canadian)
Past President, Macomb County Osteopathic Medical Association
Chairman, M.O.A. Political Action Committee
Member, Counsel of Governmental Affairs (MOA)
Vice-Chair MOA House of Delegates (MOA)
Associate Professor of Medicine MSU-COM
Diploma. Algonac High School
B.S. Microbiology, MSU
B.S. Pharmacy, Ferris State College
MSU College of Osteopathic Medicine
Hospital Orderly (Orthopedics), Ingham Medical Center
Pharmacist, Children's Hospital of Michigan
Intern, Detroit Osteopathic Hospital / BCCH
Resident, Internal Medicine, Henry Ford Hospital, Detroit
Infectious Disease Fellowship, Henry Ford Hospital, Detroit
IDSA:
Antibiotic
Stewardship
Coordinated Interventions
Designed to Improve and
Measure the Appropriate use of
Antimicrobials
By promoting the selection of the “Optimal”
antimicrobial Drug Regimen, Dose, Duration
of therapy, and Route of Administration.
*Promoting Antimicrobial Stewardship in Human Medicine Infectious Disease Society of America
http://www.idsociety.org/Stewardship_Policy/#sthash.7G8b9Xis.dpufhttp://www.idsociety.org/Stewardship_Policy/ (Accessed 7/7/2015)
Antibiotic Stewardship
Needs Assessment
• RECOGNIZING: Antimicrobial resistance has emerged as a significant
Healthcare Quality and patient Safety issue
• APPRECIATING: Dwindling Antimicrobial options.
(critical threat to the public health of the United States.
• OPPORTUNITY: Antimicrobial stewardship Programs Optimize
antimicrobial use to achieve the best clinical outcomes
- Minimizing Adverse Infection Events
- Limit Selective Pressures Driving the Emergence of Resistance
• COST EFFECTIVE: Reduce Excessive Costs
Attributable to Suboptimal Antimicrobial use
Promoting Antimicrobial Stewardship in Human Medicine
http://www.idsociety.org/Stewardship_Policy/
As Humans Evolve…..
…..So do Bacteria
Antibiotic Resistance
Historical perspective
1,2
“Antibiotic resistance is hard-wired
into bacteria”
It could be billions of years old,
but we have only been trying to
understand it for the last 70 years" 1
- Dr. Gerry Wright, PhD
“… A sample of the Culturable Microbiome* of Lechuguilla Cave, New Mexico:
•
A region of the cave that has been isolated for over 4 million years….
•
Sample of Surface microbes, were Highly resistant to Antibiotics…
•
Some strains were Resistant to 14 Different commercially available Antibiotics”
*A microbiome is the totality of microbes, their genetic elements (genomes), and environmental interactions in a particular
environment -Joshua Lederberg
1 Antibiotic Drug-Resistant Cave Bacteria Found Posted by Pharmaceutical International's Global Correspondent on 12/04/2012 http://www.pharmaceutical-int.com/news/antibiotic-drug-resistant-cave-bacteriafound.html
2 Bhullar K, Waglechner N, Pawlowski A, Koteva K, Banks ED, et al. (2012) Antibiotic Resistance Is Prevalent in an Isolated Cave Microbiome. PLoS ONE 7(4): e34953. doi:10.1371/journal.pone.0034953
Antibiotic Resistance
Implications Antibiotic Resistance
Cohen;
Science1992;257:1050
Emergence of Antibiotic-Resistant Bacteria
 Hospital- acquired
S. aureus
Gram Negative Rods
Enterococcus sp.
 Community-acquired
Shigella sp.
N. gonorrhoeae
H. influenza
M.catarrhalis
S. pneumonia
1950
1960
1970
1980
1990
Drug Resistance:
Antimicrobial Resistance: Global Report on
Surveillance 2014
http://www.who.int/drugresistance/documents/surveillancereport/en/
(Accessed 5/5/2014)
Antibiotics
Drug Resistance:
Antimicrobial resistance:
Global Report on Surveillance 2014
•
All regions of the world are experiencing resistance to carbapenem antibiotics for treatment of
Klebsiella pneumoniae, a major cause of hospital-acquired infections including pneumonia,
bloodstream infections, and infections in newborns and intensive care unit patients. Carbapenem
antibiotics are last-resort treatment for K pneumoniae and are ineffective in more than half of those
treated for K pneumoniae infections in some countries.
• Resistance to Fluoroquinolones, one of the most commonly used antibiotics for the treatment of
Escherichia coli–caused urinary tract infections, is very widespread. Fluoroquinolones are now ineffective
in more than half of patients in some countries.
•
Third-Generation Cephalosporins, the last-resort treatment for Gonorrhea, have been found to be
ineffective in Austria, Australia, Canada, France, Japan, Norway, South Africa, Slovenia, Sweden, and the
United Kingdom. At least 1 million people are infected with gonorrhea around the world every day.
•
Antibiotic Resistance causes patients to be ill longer and increases the risk for death. It is estimated that
patients with methicillin-resistant Staphylococcus aureus are 64% more likely to die than those with a
nonresistant form of the infection. Healthcare costs are increased in patients with antimicrobial-resistant
infections because of longer hospital stays and the need for more intensive care.
Antibiotic Stewardship
Clinical Stake Holders
Basic
Human
Medicine
Bacteria Infection
Resistance
Morbidity
Mortality
Veterinary
Public
Medicine
Health
Antibiotic Stewardship
Clinical Stake holders
OVERSITE AND REGULATION
Basic




•
•
Physicians / RN Practitioners & PAs
Respiratory Therapy
Pharmacy
RN / Health Aids etc.
•
Professional Organizations
Local State National: Public Health
Agencies
Local, State, Federal Government
Health
Care
Providers
Bacteria Infection
Resistance
Morbidity
Mortality
Health Care
Health Care
Facilities
Payers
 Clinical Microbiology
 Infection Prevention Policies and Practice
 Environmental services
 Private
 Governmental Agencies
Antibiotic Stewardship
Policy Statement on
Antimicrobial Stewardship
SHEA IDSA ICHE

Society for Healthcare Epidemiology of
America

Infectious Diseases Society of America

Pediatric Infectious Diseases Society

Infection Control and Hospital
Epidemiology
Policy Statement on Antimicrobial Stewardship by the Society for Healthcare Epidemiology of
America (SHEA), the Infectious Diseases Society of America (IDSA), and the Pediatric
Infectious Diseases Society (PIDS). Vol. 33, No. 4, Special Topic Issue: Antimicrobial
Stewardship (April 2012), pp. 322-327
http://www.jstor.org/stable/10.1086/665010#full_text_tab_contents
Antibiotic Stewardship
RECOMMENDATIONS
Professional Societies
PROGRAM DESIGN GOALS
1. Antimicrobial Stewardship Programs Should Be Required through
Regulatory Mechanisms. (Local / State/ National)
2. Antimicrobial Stewardship Should Be Monitored in
Ambulatory
Healthcare Settings
3. Education about Antimicrobial Resistance and Antimicrobial Stewardship
Must Be Accomplished: Health care Providers / Patients / Public
4. Antimicrobial Use Data Should Be Collected and Readily Available:
-Both Inpatient and Outpatient Antimicrobial Stewardship programs
COST EFFECTIVE PROGRAMS
September 18, 2014
President Barack Obama
(Executive Order 13676)
“The National Action Plan
for Combating AntibioticResistant Bacteria”
Developed by the interagency
Task Force for Combating
Antibiotic-Resistant Bacteria in
response to Executive Order
“The National Action Plan for Combating
Antibiotic-Resistant Bacteria”
Task Force
DEPARTMENT SECRETARIES:

Defense, Agriculture, and Health and Human Services
DEPARTMENTS

State, Justice, Veterans Affairs,

Homeland Security

Environmental Protection Agency
AGENCIES

United States Agency for International Development

Office of Management and Budget

Domestic Policy Council

National Security Council

Office of Science and Technology Policy

National Science Foundation
NATIONAL ACTION PLAN FOR COMBATING ANTIBIOTIC-RESISTANT BACTERIAIAhttps://www.whitehouse.gov/sites/default/files/docs/national_action_plan_for_combating_antibotic-resistant_bacteria.pdf
(Accessed: 8/27/2015)
Polity Plans and Objects
“The National Action Plan for Combating AntibioticResistant Bacteria”
Roadmap to guide the Nation in rising to the challenge of antibiotic resistance
Policy Plans
Object
Outlines Federal activities over the next
Five years:
Enhance Domestic and International
Capacity to prevent and contain
outbreaks of Antibiotic-Resistant
Infections
Maintain the efficacy of Current and
New Antibiotics :
Develop and deploy next-generation:
• Diagnostics
• Antibiotics
• Vaccines
• Other therapeutics
“Doubling” the amount of Federal funding for combating and preventing antibiotic
resistance to more than $1.2 billion
NATIONAL ACTION PLAN FOR COMBATING ANTIBIOTIC-RESISTANT BACTERIAIAhttps://www.whitehouse.gov/sites/default/files/docs/national_action_plan_for_combating_antibotic-resistant_bacteria.pdf
(Accessed: 8/27/2015)
Objects & Goals
“The National Action Plan for Combating
Antibiotic-Resistant Bacteria”
The Goals of the National Action Plan Include:
 Slow the Emergence of Resistant Bacteria and Prevent the Spread of Resistant
Infections
 Strengthen National One-Health Surveillance Efforts to Combat Resistance
 Advance Development and Use of Rapid and Innovative Diagnostic Tests for
identification and Characterization of Resistant Bacteria
 Accelerate Basic and Applied Research and Development for New Antibiotics, Other
Therapeutics, and Vaccines
 Improve International Collaboration and Capacities for Antibiotic-resistance
Prevention, Surveillance, Control, and Antibiotic Research and Development
-FACT SHEET: Obama Administration Releases National Action Plan to Combat Antibiotic-Resistant Bacteria
https://www.google.com/search?site=&source=hp&q=obama+antibiotic+stewardship&oq=obama+antibiotic&gs_l=hp.1.1.0l3.20488.31442.0.33938.25.17.3.5.6.0.147.1806.4j13.17.0....0...1c.1.64.hp..2.23.1700
.0.IStFTSPFCuo
-NATIONAL ACTION PLAN FOR COMBATING ANTIBIOTIC-RESISTANT BACTERIAIAhttps://www.whitehouse.gov/sites/default/files/docs/national_action_plan_for_combating_antibotic-resistant_bacteria.pdf
(Accessed: 8/27/2015)
Bacteria
Fungus
ANTIBIOTICS
“Against Life”*
*1889 by Louis Pasteur's pupil Paul Vuillemin (1861–1932
 Single “Scoop” of soil, Bacteria and Fungi number in the Millions.
 With Thousands of Varieties, and survive by “fighting” each other.
 Past century, several newly discovered Antibiotics have been
found by isolating them from the Bacteria and Fungi that produce
them to defend their own lives.
*History of Antibiotics http://inventors.about.com/od/pstartinventions/a/Penicillin_2.htm
Antibiotics :
Naturally Occur in the environment
Most available today are “Man made” from previous
Antibiotics…
AND therefore, to the Medicinal purists…are considered
Chemotherapeutic agents…
Over 60 years the world has been searched and
scoured…virtually Hundreds of compounds from all over
the world have been discovered and evaluated….
Some Great….Some NOT so Good….
Antibiotic Stewardship
GOALS
Regarding Antibiotics
• Achieve Optimal Clinical Outcomes
• Minimize Toxicity and other Adverse Events
• Reduce Infections in Health Care
• Limit the Selection for Antimicrobial Resistant Strains.
Promoting Antimicrobial Stewardship in Human Medicine
http://www.idsociety.org/Stewardship_Policy/
Antibiotics DO NOT CURE an Infection:
You must have a “Reasonably”
Functioning Immune system
Immunity:
Is the “balanced state” of having Adequate Biological
Defenses to Fight Infection, disease…
-OrOther unwanted Biological Invasion,
while having adequate tolerance to avoid Allergy, and Autoimmune Diseases.
https://en.wikipedia.org/wiki/Immunity_%28medical%29
Antibiotic Goals:
Control / “Eliminate” Infecting Organism
Both antibiotic types are effective:
• BACTERICIDEL Antibiotic
• BACTERIOSTATIC Antibiotic
Antibiotic
Immune
Response
Time
Bacterial Mass
Bacterial Mass
Antibiotic
Immune
Response
Time
Bacteria:
Race for Life
Bacteria Vs. Immune System
Metabolic Organism Maintenance:
 Bacteria “Age” and prepare to replicate
 Repair Cell Damage: DNA, Cell Wall, Internal Organelles etc.
 Replace used Enzymes: Structural, Metabolic proteins etc.
Repair Cell Aging
Damage:
•
•
•
•
Replace Enzymes Consumed
Repair DNA Damage
Repair Cell Wall Damage
Repair (Replace) Organelle Damage
Replication (Optimum environment):
“Healthy” Bacteria Cell Divide every 20
minutes:
Must produce Enough Cell wall, Structural and Metabolic proteins for
TWO cells
 Structural (Cell Wall); Metabolic Proteins, Lipids and Enzymes
 Enzymes:
Energy…. Proteins Lipids… Carbohydrates
 Enough DNA for TWO Cells
Bacterial Anatomy
And
Physiology
Structural components:
 Organelles
 Cell Wall
Carbohydrates, Lipids, Proteins, Lipoproteins
Metabolic Proteins “Life”:
Enzymes: Protein, Lipid,
Carbohydrate synthesis
Energy Production
Bacteria Anatomy
Potential Antibiotic targets
Cell wall
Exoskeleton
DNA
Cell replication
Cell function
Metabolic DNA
Plasmid
1940 - 2009
Antibiotic targets
Bacteria
Ribosome 50s:




DNA:
 QUINOLONE
 METRONIDAZOLE
 RIFAMPIN
CLINDAMYCIN
TETRACYCLINES
MACROLIDES
BIAXIN /ZITHROMAX
 LINEOZOLID (23s)
AMINOGLYCOSIDES
30S
Anti-metabolites:
Plasmid
Sulfonamides
Membrane
Detergents
 Daptomycin
Cell Wall:
 BETA LACTAMASES
 GLYCOPEPTIDES
1940 - 2014
Ribosome:
 Structural proteins,
 Metabolic proteins
• Cell Repair
• Daughter cells
Antibiotic Resistance
Mechanisms : Acquisition of Resistance
“Mobile Genetic Elements”
Plasmids (1940 - 2015)
1940 Westergard Mercury
 Are (typically) Circular Double - Stranded DNA
molecules.
 Separate from the Chromosomal DNA.
 Size varies from 1 to over 400 kilo-base (kbp).
•
•
EACH BACTERIA CELL:
Anywhere from one copy, (For large plasmids) to
hundreds of copies of the same plasmid
A variety of resistance factors are found:
β-lactamase
Extended Spectrum β lactamase (ESBL)
All Ribosomal active agents
2015 Ferrari 458
In 1918….
H1N1 Influenza circled to globe 3 times in 18 months
using 1918 Transportation Systems…..
Let the GAMES
begin….
1880
Before the Germ Theory….
“EVIL TUMORS and VAPORS”
Puerperal fever, also known as “Child-bed fever“:
•
•
Physicians did not scrub before surgery or wash their hands
between patients
Doctors and Medical students routinely moved from Dissecting
Corpses to examining New Mothers without first Washing their
hands…
Puerperal Fever:
•
•
•
•
Common in hospitals and often fatal, with mortality at 10%–35%.
Autopsies showed a confusing multitude of physical signs, which
emphasized the belief that puerperal fever was not one, but many
different, yet unidentified, diseases.
Conventional wisdom that diseases spread in the form of “Bad
Air", also known as miasmas or vaguely as "un-favorable
atmospheric-cosmic-terrestrial influences"
“And, with due respect for the cleanliness of the Viennese
Students, it seems improbable that enough infective matter or
vapor could be secluded around the fingernails to kill a patient."
Vienna General Hospital
1880
Before the Germ Theory….
Puerperal fever, also known as "childbed fever"
In 1840’s (1847) while the Director of the maternity clinic at the Vienna
General Hospital in Ignaz Philliop Semmelweis (a Hungarian physician)
demonstrated that hand-washing with a chlorinated lime solutions
could drastically reduce the number of women dying after childbirth.
(35% Mortality to <1%)
Ignaz Phillip Semmelweis 181865
Beginning in 1861, Semmelweis
suffered from various nervous
complaints, severe depression, and
became absentminded.. On July 30,
1865 he was lured to a Viennese
insane asylum. He tried to leave, was
severely beaten by several guards;
secured in a straitjacket, and
confined to a darkened cell. (Mental
institution therapy included dousing
cold water, castor oil, and enemas).
He died after two weeks, (August 13,
1865, aged 47), from a gangrenous
wound- possibly caused by the
beating. The autopsy gave the cause
of death as “pyemia”—blood
poisoning
However his observations conflicted with the established Scientific and
Medical opinions of the time:
• His ideas were rejected by the medical community.
• Some doctors were offended at the suggestion that they should wash
their hands
• Semmelweis could offer no acceptable scientific explanation for his
findings
We all now know how important it is to wash our hands:
•
•
•
In hospitals, bacteria are wiped out by the simple act of hand-washing.
Wards are supplied with Antiseptic Hand Gel, medical staff and visitors use before they
see patients
Routine of ‘scrubbing up’ by surgeons before an operation is, a well-established practice.
Semmelweis, Ignaz
Bibilography
•
•
•
•
•
•
•
Semmelweis, Ignaz; Carter, K. Codell (translator, extensive foreword) (September 15, 1983)
[1861], Etiology, Concept and Prophylaxis of Childbed Fever, University of Wisconsin Press,
ISBN 0-299-09364-6 (references to Carter's foreword and notes indicated "*")
Carter, K. Codell; Carter, Barbara R. (February 1, 2005), Childbed fever. A scientific biography
of Ignaz Semmelweis, Transaction Publishers, ISBN 978-1-4128-0467-7
Ignaz Semmelweis From Wikipedia, the free encyclopedia
https://en.wikipedia.org/wiki/Ignaz_Semmelweis#cite_note-Carter1-13
Dr. Semmelweis’ Biography Semmelweis Society International
http://semmelweis.org/about/dr-semmelweis-biography
M Best, D Neuhauser, Heroes and martyrs of quality and safety Ignaz Semmelweis and the
birth of infection control Qual Saf Health Care 2004;13:233-234
doi:10.1136/qshc.2004.010918
Howard Markel. In 1850, Ignaz Semmelweis saved lives with three words: wash your hands
PBS News hour. http://www.pbs.org/newshour/author/hmarkel/
John H. Lienhard No. 622: IGNAZ PHILIPP SEMMELWEIS.Engines of our ingenuity
http://www.uh.edu/engines/epi622.htm
1935:
THE AGE OF
ANTIBIOTICS
BEGINS:
Age of Sulfonamides
Time Line I
Year
Historical Factoid
1909
Paul Gelmo, a chemistry student working at the University of Vienna in his 1909 thesis, first synthesized. although
he had not realized its medical potential [Prontosil® (Sulfonamidochrysoidine)]
1931
Josef Klarer and Fritz Mietzsch: synthesized Prontosil® (Part of a research program designed to find dyes that
might act as systemic antibacterial drugs).
Theory : Coal-tar dyes which are able to bind preferentially to bacteria and parasites might be used to attack
harmful organisms in the body.
1932
*IG Farben filed a German patent application concerning Prontosil® medical utility
1932
Prontosil® was found effective against some important bacterial infections in mice by Gerhard Domagk
19321934
Prontosil Solubile®, clinically investigated between 1932 and 1934, at Wuppertal-Elberfeld Hospital and Düsseldorf
university hospital (Philipp Klee)
1935
Feb
The study results published in a series of articles (February 15, 1935) Deutsche Medizinische Wochenschrift, [5]
•
Initially received with some skepticism by a medical community bent on vaccination and crude
immunotherapy.
Prontosil®
Age of Sulfonamides
Time Line II
Year
Historical Factoid
1935
Leonard Colebrook showed Prontosil was effective against Haemolytic
Streptococcus in childbirth : cure for puerperal fever.
Impressive clinical successes with Prontosil started to be reported from all over
Europe, and especially after the widely published treatment of Franklin
Delano Roosevelt, Jr…..Acceptance was quick and dozens of medicinal
chemistry teams set out to improve Prontosil.
1937
Elixir Sulfanilamide (diethylene glycol) caused mass poisoning
(United States) Deaths >100 people.
The public outcry caused by this incident (and other similar disasters) led to the
passing of the 1938 Federal Food, Drug, and Cosmetic
*IG Farben (Interessen-Gemeinschaft Farbenindustrie AG) German chemical industry conglomerate,
notorious for its role in the Holocaust. Formed in 1925; During its heyday, largest chemical company in the world and
the fourth largest overall industrial concern, after General Motors, U.S. Steel, and Standard Oil of New Jersey.
Following the Nazi takeover of Germany, IG Farben became involved in war crimes during World War II. The firm's
pro-Nazi leadership openly collaborated the Nazi government to produce the large quantities of Zyklon B. Post war,
the firm ceased operating (1945), assets were liquidated 1952; 13 executives were imprisoned for terms ranging from
1 to 8 years at the Nuremberg Trials.
Age Of Sulfonamides
Bibliography
1.
2.
3.
4.
5.
6.
The 1937 Elixir Sulfanilamide Incident“ Medicine: Post-Mortem". Time (magazine). December 20, 1937.
Defunct Companies Of Germany: IG Farben. Snip view.http://www.snipview.com/q/IG_Farben
Dunn PM. Perinatal lessons from the past Dr Leonard Colebrook, FRS (1883–1967) and the chemotherapeutic conquest of puerperal
infection. Arch Dis Child Fetal Neonatal Ed 2008;93:F246-F248 doi:10.1136/adc.2006.104448
Medicine: Prontosil, TIME Magazine, December 28, 1936 (Franklin Delano Roosevelt, Jr)
G. Domagk, "Ein Beitrag zur Chemotherapie der bakteriellen Infektionen", Deutsch. Med. Wschr., 61, 15 February 1935, p. 250
The makings of a miracle Drug. Smells like science. http://smellslikescience.com/the-making-of-a-miracle-drug/
The First recorded use of a Sulfa antibiotic drug in the
United States took place at Babies Hospital, Brooklyn
New York, July 1935.….. Dr. Alexander Ashley Weech MD
Katherine Woglon
10-year-old daughter of a Brooklyn
physician; the target was the bacterium
that caused her meningitis. (H.
influenza)
After an apparent cure, Katherine
suffered a relapse a few months later
and died.
- Eric Oatman The drug that changed the changed the world. P&S The College of Physicians and Surgeons of Columbia University,
http://www.cumc.columbia.edu/psjournal/archive/winter-2005/drug.html (Accessed 3/15/2014)
- Schwentker FF, Gelman S, Perrin HL . The Treatment of Miningococcic Meinigitis with Sulfanillamide: Preliminary JAMA. 1937;108(17):14071408
Antibiotics
Clinical Beginning (1-6)
The first test case treatment of Infections
with Penicillin 1940
Albert Alexander
(1873-1941)
•
•
•
•
•
•
September 1940, an Oxford county England police constable, Albert Alexander, 48,
working in his rose garden, “nicked” the corner of his mouth on a rose thorn.
By the end of the month, the scratch was badly infected, with both Staphylococcus
and Streptococcus.
The infection, un-responsive to Sulfonamides antibiotics, spread to his eyes, scalp,
lungs, and shoulder.
Alexander admitted to the Radcliffe Infirmary. The infection worsened despite efforts
with various treatments including Sulfa antibiotics.
Alexander's head and scalp became covered with infection, he was persistently
bacteremic, his face was matted with weeping red abscesses, and
Progressing, one of his eyes had to be removed.
1 Markel H. The Real Story Behind Penicillin. The rundown : PBS News hour. http://www.pbs.org/newshour/rundown/the-real-story-behind-the-worlds-first-antibiotic/
2 David Greenwood. Antimicrobial Drugs Chronicle of the twentieth Century Medical Triumph. Oxford University press 2008 pg 101
3 Albert Alexander. From Wikipedia, the free encyclopedia http://en.wikipedia.org/wiki/Albert_Alexander
4 "Making Penicillin Possible: Norman Heatley Remembers". Science Watch. Thomson Scientific. 2007
5 Abraham, E.P., Gardner, A.D., Chain E et al. Further Observations of Penicillin. Lancet 1941, August 16; pp 6155-66
6 The Almost -Cure All Urine of Albert Alexander. http://bmackie.blogspot.com/2012/08/the-almost-cure-all-urine-of-albert.html (Accessed 3/15/2014)
Antibiotics
Clinical Beginning (1-6)
The first test case treatment of infections with
Penicillin
Albert Alexander (1873-1941)
• Howard Florey and Boris Chain heard about the horrible case and asked the
Radcliffe physicians if they could try their “purified” penicillin.
• On February 12, 1941 Mr. Alexander began receiving Penicillin: the Initial dose
was 200 Units (160mg), then 100 mg every 3 hours.
• After five days of injections, Alexander began to recover. But Chain and Florey
did not have enough penicillin to eradicate the infection; the Penicillin ran out
on February 17, 1941 (Despite recycling Penicillin from the Alexander’s urine
(6)).
• Mr. Alexander ultimately died of an overwhelming Staphylococcal sepsis on
March 15, 1941.
1 Markel H. The Real Story Behind Penicillin. The rundown : PBS News hour http://www.pbs.org/newshour/rundown/the-real-story-behind-the-worlds-first-antibiotic/
2 David Greenwood. Antimicrobial Drugs Chronicle of the twentieth Century Medical Triumph. Oxford University press 2008 pg 101
3 Albert Alexander From Wikipedia, the free encyclopedia http://en.wikipedia.org/wiki/Albert_Alexander
4 "Making Penicillin Possible: Norman Heatley Remembers". Science Watch. Thomson Scientific. 2007
5 Abraham, E.P., Gardner, A.D., Chain E et al. Further Observations of Penicillin. Lancet 1941, August 16; pp 6155-66
6 The Almost -Cure All Urine of Albert Alexander http://bmackie.blogspot.com/2012/08/the-almost-cure-all-urine-of-albert.html (accessed 3/15/2014)
Antibiotics
History: Penicillin in America
1,2,3,4
Anne Sheafe Miller (1909 -1999)
In March 1942
33-year-old Anne Sheafe Miller
• Wife of the Yale Athletic Director, Ogden D. Miller
• 1931 Graduate of Columbia Presbyterian School of Nursing, (Now part of Columbia
University).
Hospitalized for almost one month, lay dying of β-Hemolytic Streptococcus “Puerperal
sepsis”,
(S pyogenes) following a miscarriage, in a New Haven, Connecticut hospital.
Despite the best efforts of contemporary medical science:
Sulfa antibiotics, Blood Transfusions, and several Surgeries, She remained Delirious, Febrile
(103-1060 F) and Bacteremic.
Her physician John Bumstead, M.D. could not eradicate her bloodstream infection………
1 Curtis J. Fulton, Penicillin and chance. Yale Medicine. http://yalemedicine.yale.edu/autumn1999/features/capsule/55396 (Accessed 3/15/2014)
2 David Greenwood. Antimicrobial Drugs Chronicle of the twentieth Century Medical Triumph. Oxford University press 2008 pg 1014)
3 Tager M. John F. Fulton, coccidioidomycosis, and penicillin. Yale J Biol Med. 1976 Sep;49(4):391-8.
4 Grossmen CM. The First Use of Penicillin in the United States Ann Intern Med. 2008;149:135-136.
Serendipitously:
Mrs. Miller’s physician, Dr. Bumstead was treating a colleague Dr. John Fulton, who was hospitalized
at the same time - with Pulmonary Coccidioidomycosis .
Dr. Bumstead approached his patient (Dr. Fulton) with a plea: He was ware of
Fulton’s friendship with Dr. Howard Florey, (Clinically developing Penicillin) and
asked Fulton if he could talk to Florey, and obtain for a sample of Penicillin for
treatment of the infection. Several phone calls later (Merck & Co) the antibiotic
was procured.
Dr. Norman Heatley, (Biochemist developing Penicillin) a colleague of Dr. Florey
from Oxford University UK, brought the vial of Penicillin (5.5 grams) to New
Haven (From Merck & Co in Rahway, New Jersey.)
(3)
Intern, Herbert Tabor, M.D., was responsible for injecting the drug, and recycling Miller’s urine (Sent Merck & Co), where up to 70% of
the scarce and costly drug could be recovered and reused.
Penicillin: The Miracle Drug Clinical Research at Yale, Yale School of Medicine http://www.yalestudies.org/clinicalTrials/page.asp?p=penicillin
History: Penicillin in America
Anne Sheafe Miller
- Curtis J. Fulton, Penicillin and Chance. Yale Medicine.
http://yalemedicine.yale.edu/autumn1999/features/capsule/55396 (Accessed 3/15/2014)
- Grossmen CM. The First Use of Penicillin in the United States Ann Intern Med. 2008;149:135-136.
.
Hemolytic Streptococcal Septicemia
108
10
6
10
Rectal
4
Temperature 102
O
10
F
0
9
8
A
Blood Culture
B
Units/Day x
1000
Sulfadiazine
Grams/Day
Hospital
Week
40
3
0
20
1
0
First
Operation
Penicilli
n
Second
Operation
Colonies/ml
Anne Sheafe Miller
(1909-1999)
with
Alexander Fleming,
6
3
1
2
3
4
5
6
7
8
Miller began receiving her first dose via intravenous drip at 3:30 p.m. on a Saturday. (10-40,000 Units/Day)
A The next morning her temperature, which had hovered between 103 and 106.5 degrees, dropped to
normal for the first time in four weeks.
B Her Blood bacteria count dropped (Quantative)
 By Monday her appetite had returned and she had eaten four full meals.
Levine DP, Vancomycin: A History. CID 2006:42 (Suppl 1), S5-S12
Edmund Carl Kornfeld
1919 –2012
November 21, 1961,
Michael C. Rockefeller, 23year old
Beta-lactams
β-lactam
Monobactam
(Azetreonam)
Cephalosporins
penicillin
Carbapenems
“Pus”:
• A protein-rich fluid called “Liquor puris” usually
Whitish-Yellow, Yellow, or Yellow Brown in color.
• Pus consists of a buildup of Dead leukocytes
(White Blood Cells) from the body's immune
system in response to infection.
• It accumulates at the site of inflammation.
http://www.medicalnewstoday.com/articles/249182.php
One “Loop-full” (“Drop”) of Suspended
S. aureus colony contains 250,000 organisms…
 Loop = 1 drop
 20 drops in 1 cc (cm³).
 1cc ~ 5.0 million Bacteria
MRSA
Genome
• 1 : 250,000 contain the
•
mecA 2a Genetic Mutation
• The Bacterial Cell and Daughter Bacteria Cells
•
will be Resistant to…….
•
ALL BETA LACTAM Antibiotics *
*Remains Sensitive to Vancomycin:
ANY De-novo MUTATIONAL attempt for S. aureus
to become resistant to Vancomycin is a Lethal event
to the Bacteria….(VANCOMYCIN : “Ace in the
Hole”).
Chromosome
I
Bacterial Cell wall
II2a
Methicillin Resistant
“MRSA”
mec
A
V
III
IV
Peri-plasma
space
VI
PLASMA MEMBRAME
PBP
CELL WALL
Peptidoglyca
n
β-lactamases
1964 Likely “Original” MRSA
infections developed in
Immunocompromized; Hospitalized
patients with Methicillin Sensitive
(MSSA) infections.
Antibiotics eliminated the Penicillin
“Sensitive Bacteria”….
….
1970’s the MRSA organisms
“escaped” the hospital and began
infecting and colonization the General
Population……
In their “Weaken” Immune state
the patients could not clear the
residual Methicillin Resistant
(“MRSA”) Bacteria leading to
“Super” Infections…
S. Aureus
Epidemiology: Human Carriers
S aureus:
“Uniquely” a Human Bacteria
30 - 40% Healthy Human Carriers
(Any given time)
1%
Humans are MRSA Carriers
300 Million Americans:
100 Million MSSA carriers
1 million MRSA Carrier
Transmission:
Close personal contact
Infected secretions (“Pus”) / Objects
Skin Contact (Athletic competition, Draining lesions)
Shared Personal items (Towels, Razors, Medical Equipment etc.)
2002
It must be a “Spider bite”….
…..What else could it be?
U.S. Geographic Distribution of Verified Widespread Populations of Six Native Loxosceles Species.
Loxosceles spiders purportedly are transported beyond the areas where they are endemic in
household goods and warehouse cargo…but uncorroborated… actual epidemiology essentially
does not occur beyond the spiders' usual habitat.
Where Did all this Community Acquired
CA-MRSA Come from?
MRSA Hospital
1960-1970s
“Community Staph”
MSSA
Increased Virulence
“Staff-ala-roar-e-us”
“Staff-full-of-oreos”
Community
MRSA
(USA 300)
2000
 Panton-Valentine leukocidin genes
 Expression of core genome-encoded
toxins
Creatures Walk
Among Us
Creatures Walk Among Us
Multidrug-Resistant “MDR” : Pneumococci,
Gonococci, and Salmonella spp
Extremely Drug-Resistant Tuberculosis
(MDRTD, XDRTB)
Vancomycin-Resistant Enterococci “VRE” (and
Vancomycin-Resistant S. aureus “VRSA”
Extended-Spectrum Beta-Lactamase “ESBL”Enterobacteriaceae, Pseudomonas aeruginosa
Carbapenemase-Producing Klebsiella
pneumonia
Pan-Resistant: Acinetobacter baumanii
Gram Positive Bacteria
Skin Mucus Membrane
Gram Negative Bacteria
Enterobacteriaceae
(Human GI Flora)
Gram Negative Bacteria
Environmental
And
Contagious bacteria
(Pulmonary, STD’s etc)
Hans Christian Gram
Wikipedia, the free encyclopedia
Hans Christian Joachim Gram
Danish bacteriologist
Gram studied Botany at the University of Copenhagen and assisted
Japetus Steenstrup. His interest in plants introduced him to the basis of
pharmacology and the use of the microscope.
•
•
He entered medical school in 1878 and graduated in 1883. He traveled
throughout Europe between 1878 and 1885. In Berlin in 1884, he
developed a method for distinguishing between two major classes of
bacteria. This technique, the Gram Stain, continues to be a standard
procedure in medical microbiology.
In 1891, Gram became a lecturer in pharmacology, and later that year
was appointed professor at the University of Copenhagen. In 1900 he
resigned his Chair in Pharmacology to become Professor of Medicine
The Gram Stain
•
The work that gained him international reputation was his development
of a method of staining bacteria. The stain later played a major role in
classifying bacteria
• Gram was a modest man, and in his initial publication he remarked
"I have therefore published the method, although I am aware that as yet
it is very defective and imperfect; but it is hoped that also in the hands of
other investigators it will turn out to be useful".
Hans Christian Joachim Gram
September 13, 1853 - November 14, 1938
Edwin Kleb*
(2/6/1834 – 10/23/1913)
German physician and Bacteriologist noted for his work on the
Bacterial Theory of infection:
•
•
•
Assistant to Rudolf Virchow (Pathological Institute, Berlin 1861–66).
Rush Medical College (1896).
Preceded Robert Koch in studying the bacteriology of traumatic
infections,
• 1876: Succeeded in producing endocarditis by mechanical means
combined with general infection
• Tuberculosis : Was able to produce bovine infection by means of milk.
• 1878: Successfully transmitted syphilis to monkeys
Studied:
• Malaria, Hemorrhagic pancreatitis, and Gigantism.
Published:
Monographs and Articles; Handbook of pathological anatomy (1869–76)
Teatise on general pathology (1887–89).
(Died from Tuberculosis)
* Encyclopedia Britannica http://www.britannica.com/EBchecked/topic/319924/Edwin-Klebs
Antibiotic Resistance
Human/Bacterial Ecology
Important Human pathogens
Gram Positive
Gram Negative
(Skin, Mucus Membranes)
(Enterobacteriaceae GI Tract)
S. aureus (MSSA,MRSA,VRSA,CA-MRSA)
S. epidermidis
STREPTOC0CCI
S. pyogenes (β Streptococci)
S. agalactiae (β Streptococci)
Pneumococcus
Enterococcus (GDE,VRE)
Viridian streptococcus Group
I. E. coli
II. Salmonella, Shigella
III. Proteus, Morganella
IV. Klebsiella, Serratia,
Enterobacter sp. (KES)
V.
Yersinia
Anaerobic Gram Negative:
Cocci, Rods, Spiral
(Environmental)
Five tribes:
H. influenza
Anerobic Bacteria:
Gram Negative
Bacteroides sp.
P. aeruginosa
Aeromonas sp.
Acinetobacter sp.
Question 121
A 52-year-old woman called her physician and reported
Urinary Frequency and Urgency, Mild fever, Nausea
accompanied by Supra pubic pain.
UA
Results
Protein
Positive
Glucose
Negative
Ketones
Negative
Leukocyte Esterase
Positive
Nitrates
Positive
WBC
Too Numerous To
Count
K. pneumonia
Question
She completed a three-day course of ciprofloxacin, but her
symptoms did not improve. Bacterial Urine Culture were
positive for K. pneumonia.
Which of the following details of the patient's
history may have put her at risk for this
infection?
(A)
She received levofloxacin for urinary tract infections at two
separate times during the past year.
(B) She received breast implants in Brazil three
months ago.
(C) She accompanied her husband to India, where
he underwent knee surgery six months ago.
(D) She is of Korean origin, and she traveled to Korea to
visit family and friends six months ago.
Antibiotic
Suscepti
ble
Resistant
Imipenem
-
X
Meropenem
-
X
Piperacillin/
Tazobactam
-
X
Cefotaxime
-
X
Ceftazidime
-
X
Cefpirome
-
X
Aztreonam
-
X
Ciprofloxin
-
X
Gentamicin
-
X
Tobramycin
-
X
Amikacin
-
X
Minocycline
-
X
Tigecycline
X
-
Colistin
X
-
New Delhi metallo-lactamase-1
Question 121
•
•
•
•
•
•
The carbapenem resistance, broad cross-class resistance, and susceptibility only to
Tigecycline and Colistin of this member of the Enterobacteriaceae are
characteristic of the New Delhi metallo-beta-lactamase 1 (NDM-1).
Among the confirmed cases of NDM-1, the majority of those who have sought care
have traveled to India or Pakistan and been hospitalized within those countries.
The encapsulated Klebsiella bacteria known to cause serious deep and metastatic
infection in persons of East Asian (including Korean) descent have generally not
been highly resistant organisms.
There have been outbreaks due to Mycobacterium fortuitum and other rapidgrowth mycobacteria in association with breast implants in Brazil as well as in the
United States and other countries.
Brazil, moreover, has a high prevalence of resistant gram-negative organisms;
therefore, exposure to Brazilian healthcare is a potential but as yet unreported risk
for cases of resistant infection in the United States.
There are also documented cases of patients who have undergone plastic surgery in
India and returned with NDM-1 infection.
For further information, see the following:
1. Kumarasamy KK, Toleman MA, Walsh TR, Bagaria J, et al . Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a
molecular, biological, and epidemiological study. Lancet Infect Dis Sep 2010;10(9):597-602.
2. Rossi F. The challenges of antimicrobial resistance in Brazil. Clin Infect Dis May 2011;52(9):1138-1143
New Delhi metallo-lactamase-1
“Gram-negative Enterobacteriaceae with resistance to carbapenem
conferred by New Delhi metallo-β-lactamase 1 (NDM-1) are potentially a
major global health problem.
Highly resistant to many antibiotic classes, potentially herald the end of
treatment with β-lactams, fluoroquinolones, and aminoglycosides—the
main antibiotic classes for the treatment of Gram-negative infections” *
* Kumarasamy, KK, Toleman MA, Walsh TR et al. Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular,
biological, and epidemiological study Lancet Infect Dis. 2010 September; 10(9): 597–602.
New Delhi metallo-lactamase-1
Emergence/Recognition
Year
Factoid
19961
metallo-β- lactamase-producing Klebsiella pneumoniae Singapore
2008
NDM-1 detected in a K. pneumoniae isolate from a Swedish patient of Indian origin in 2008.
2008
NDM-1 Detected in bacteria in India, Pakistan, the United Kingdom 2008
2010
- United States
- Canada
- Japan
- Brazil
(September )
(August)
(September)
(October)
Australia, Belgium, Canada, Germany, Hong Kong, Japan, Kenya, the Netherlands, Norway,
2010
December Oman, Singapore, Sweden, Taiwan, and the USA, Denmark.*
*Most of these patients also had direct links to Asia
2
1 Koh TH, Babini GS, Woodford N, Sng LH, Hall LM, Livermore DM. Carbapenem hydrolysing IMP-1 beta-lactamase in Klebsiella
pneumoniae from Singapore. Lancet 1999; 353: 2162.
2 Hammerum AM, Toleman MA, Hansen F, etal. Global spread of New Delhi metallo-β-lactamase 1 .The Lancet Infectious
Diseases, Volume 10, Issue 12, Pages 829 - 830, December 2010
New Delhi metallo-lactamase-1
Emergence/Recognition
First death
(AFP) – Aug 13, 2010
• August 2010, the first reported death due to bacteria
expressing the NDM-1 enzyme was recorded.
• Belgian man, become infected while being treated in a
hospital in Pakistan, died despite being administered
Colistin.
• Doctor involved in his treatment said: "He was involved in
a car accident during a trip to Pakistan.
• He was hospitalized with a major leg injury and then
repatriated to Belgium, but he was already infected".
Belgian man dies of South Asian superbug (AFP) – Aug 13, 2010http://www.google.com/hostednews/afp/article/ALeqM5g2UVNIO5tUQAqbWeE7l2PjSW34cg
THE
PARADOX
Scientists, (Microbial genetics,
Mathematicians, Bio-chemists,
Pharmacologists, Pharmaceutical
Chemists, Microbial geneticists:
Will tell you….
It is IMPOSSIBLE for ANY bacterial
organism especially Staphylococcus
to develop resistance to
VANCOMYCIN……
Vancomycin Resistant Enterococcus
“VRE”
Europe 1980s……..
* Uttley AH, Collins CH, Naidoo J, George RC (1988). "Vancomycin-resistant enterococci". Lancet 1 (8575-6): 57–8
**Leclercq R, Derlot E, Duval J, Courvalin P (July 1988). "Plasmid-mediated resistance to Vancomycin and teicoplanin in Enterococcus faecium". N. Engl.
J. Med. 319 (3): 157–61.
S. Aureus:
Vancomycin is the
Therapeutic
“Ace in the Hole”
ALL
S. aureus are Sensitive to Vancomycin…
ANY
“Intrinsic” organism attempt to develop
Mutational resistance
IS a Lethal Mutational event……
“VRE”
“Van A”
gene
“MRSA”
Vancomycin
1992*
“VRSA”
Vancomycin Resistant
S. aureus
* Noble WC, Virani Z, Cree RG (June 1992). "Co-transfer of vancomycin and other resistance genes from Enterococcus faecalis” NCTC 12201 to
Staphylococcus aureus". FEMS Microbiol. Lett. 72 (2): 195–8
Can you Imagine a world….
Where there are NO antibiotics
available to treat S. aureus
Infections?....
Thank goodness we have
Vancomycin!........
VRSA
William Beaumont
Hospital
Royal Oak, Michigan
2002*…
* Chang S, Sievert DM, Hageman JC, et al. (April 2003). "Infection with vancomycin-resistant Staphylococcus aureus containing the vanA resistance
gene". N. Engl. J. Med. 348 (14): 1342–7.
Vancomycin Resistant S. aureus (“VRSA”)
Historical U.S. VRSA 2010 Case count and geographical information
Cas
e
State
Year
Ag
e
Source
Diagnosis
Underlying Conditions
1
MI
2002
40
Plantar ulcers &
Catheter tip
Plantar soft tissue infection
Diabetes, dialysis
2
PA
2002
70
Plantar Ulcer
Osteomyelitis
Obesity
3
NY
2002
63
Urine from a
nephrostomy tube
No Infection
Multiple Sclerosis,
Diabetes, Kidney stones
4
MI
2005
78
Toe Wound
Gangrene
Diabetes, Vascular disease
5
MI
2005
58
Surgical site wound
after Panniculectomy
Surgical Site Infection
Obesity
6
MI
2005
48
Plantar Ulceration
Osteomyelitis
MVA, Chronic Ulcers
7
MI
2006
43
Triceps Wound
Necrotizing Fasciitis
Diabetes, Dialysis, Chronic ulcers
8
MI
2007
48
Toe Wound
Osteomyelitis
Diabetes, Obesity, Chronic ulcers
9
MI
2007
54
Surgical site wound
after foot amputation
Osteomyelitis
Diabetes, Hepatic Encephalopathy
10
MI
2009
54
Plantar foot wound
Plantar soft tissue
infection
Diabetes, Obesity, Lupus,
Rheumatoid Arthritis
11
DE
2010
64
Wound Drainage
Prosthetic joint infection
Diabetes, Dialysis
Country
Iran
2005 1
# isolates
5
13 case 2014
J Clin Microbiol. 2014 Mar; 52(3): 998–1002. doi: 10.1128/JCM.02187-13
* Centers for Disease Control http://www.shea-online.org/Assets/files/newsletter/VRSA_Lab_Update.pdf
WHAT IS NEXT
INSIDE
OUTSIDE
Physician/Patient and Clinical
•
•
•
•
•
Education & Campaigns
Surveillance Systems
Laboratory Testing & Training
References & Resources availability
Antibiotic Stewart programs
Centers for Disease Control http://www.cdc.gov/drugresistance/index.html
Maybe / Yes
Research continues to Develop New Antibiotic Classes….
…. And to Extend the life of Present Antibiotics
Combinations of Antibiotics (Beta lactam / Clindamycin)
Restricting Antibiotic Policies (Hospital, 3rd Party payers)
Culturing Infections for Antibiotic Direction
Empiric Choices……
2015
A NEW DAWN?
Dirt from a Grassy Field in Maine…
PARADOX
 1% of the Microbes in the Soil (Or Sea water) can be Reliably Grown Under Lab Conditions.
 Remaining 99% Likely produce “Unknown” / Un-discovered Antibiotics
iChip technology: Eleftheria terrae
Teixobactin Inhibits Cell Wall Synthesis by Binding to a Highly Conserved Motif of Lipid II (Precursor of
Peptidoglycan) and lipid III (Precursor of Cell Wall Teichoic Acid)
If Teixobactin makes it to the market, it could be the First New Class of Antibiotic in Decades*
Gram-Positive Pathogens including S. aureus, E. faecium / faecalis, various streptococci,
M. tuberculosis, C. difficile. Teixobactin had equivalent activity to Oxacillin (Methicillin)
in vitro, and “Superior activity “ to Vancomycin both in Vitro and Animal model.
-Ling LL, Schneider T, Peoples AJ, et al. A New antibiotic kills pathogens without detectable resistance. Nature 517, 455–459 (22 January 2015) doi:10.1038/nature14098
-*New class of antibiotic found in dirt could prove resistant to resistance. https://www.washingtonpost.com/news/speaking-of-science/wp/2015/01/07/new-class-of-antibiotic-found-in-dirt-could-prove-resistantto-resistance/
Questions?