Microbial Colonization and New Resistant Organisms
Bryan Larsen, PhD
Marian University College of Osteopathic Medicine
Perspective:
Penicillin – “the first shall be last”
Colonization:
Contemporary concepts
Where it all begins, Where it stops
Cataloging the organisms of concern
The Pipeline is not the answer
Conceptualizing and Implementing
Antibiotic Stewardship
Ernst Chain
D 1979
Howard Florey
D 1968
Norman Heatley
D 2004
Alexander Fleming
D 1955
I wonder who took the wonder
out of wonder drugs?
• WWII began before we had penicillin
• The need was compelling
• Staph, strep, burn wound infection in 1940-1
Battle of Britain had no real antibiotic
• Clinical tests were based on the availability of
very few available doses
• Clinical results were spectacular
• Penicillin was deemed to be a “wonder drug”
I wonder who took the wonder
out of wonder drugs?
• Penicillin was so scarce and precious and effective
in the early days, that urine was collected and
processed to recover excreted drug
• Mid 1942 there was enough to treat 10 patients
• Chain, Florey, Heatley developed scale up in 1942
• Peoria was the location of massive fermentation
of Penicillin in Corn-steep liquid
• 1944 - 1600 billion units produced (100K
units/dose)
“Familiarity breeds contempt”
• While many drugs treated illness, few could
effect a complete “cure”
• Antibiotic therapy became commonplace
• The success of antibiotics led to eagerness to
use for expanding indications (even when
evidence was anecdotal)
• By the 1950’s there were other wonder drugs
Victims of their own success…
• Today there are hundreds of anti-infective
compounds listed in the PDR
• Experts have opined that 50% of antibiotic use
is either inappropriate or ineffective
• We will take up this controversial concept at
the close of this talk
Victims of microbial success…
• When previously susceptible microorganisms
develop the ability to resist the action of an
antimicrobial drug, use of that drug becomes
ineffective
• Development of resistance is driven (largely)
by microbial exposure to antibiotics through
selective pressure
• Eliminate antibiotic, antibiotic and you
eliminate selective pressure for resistance
Perspective:
Penicillin – “the first shall be last”
Colonization:
Contemporary concepts
Penicillin was so scarce and precious in the
Where it all
ittostops
earlybegins,
days, that urineWhere
was processed
recover
excreted drug
Cataloging the organisms of concern
The Pipeline is not the answer
Conceptualizing and Implementing
Antibiotic Stewardship
Colonization (Classical)
• Direct infection with a drug resistant is possible;
colonization prior to disease is typical
• Humans have an abundant indigenous flora at
all sites accessible to the environment
• Microbial cells outnumber human cells
• Microbial cells can be shed and survive; human
cells cannot
• The microbial flora is polymicrobial and stable
Colonization (Contemporary)
• Its not them versus us (the flora is an organ of the
human body)
• Until deep-sequencing and metagenomics the full
diversity of the flora was not appreciated
• Microbial ecology indicates there are functional
roles for organisms that are independent of species
• One functional microbial class may be the master
regulator of the normal flora
• Strain replacement may occur
• Community types may vary over time but the
mechanism is unknown
Diversity, Regulation, Stability
R. Hummelen et al PLOS1 November 2011
doi:info:doi/10.1371/journal.pone.0026602.g002
Acquisition of Antimicrobial Resistant Organisms
•
•
•
•
Confined
Community
Compromised
Changing geography
• In hospital
– Organisms exposed to
antibiotics
– Patients exposed to
sources of organisms
• Intensive care
• Long term care
• Rehabilitation center
Simultaneous Occurrences
• Antibiotics used for
therapy and present in
the hospital environment
put selective pressure on
host microflora to
increase prevalence of
resistant strains
• Resistant community
bacteria present in
patients, staff and
visitors enter the
hospital environment
Hospital activities move resistant
strains from person to per person
with potential for colonization
Long term care
• Prospective enrollment with periodic multisite culture
• 47% entered the LTC facility with CIP-R
• Time to acquisition (among non-colonized):
– CIP-R
– MRSA
– CAZ-R
– VRE
75.5 days
126.6 days
176 days
186 days
J Fisch et al. J Clinical Micro February 2012
Incidence of acquisition of ARO (MRSA, VRE,
CR-PA) per 1000 days of antibiotic treatment
Piperacillin-tazobactam
Macrolides
Glcopepetides
Quinolones
Broad Spectrum cephalosporins
Carbapenem
0
2
4
6
8
10
12
14
16
Tancrelli , et al. Antimicrob Agents Chemother 2009; 53: 4264
Acquisition of Antimicrobial Resistant Organisms
•
•
•
•
Confined Patients
Community Populations
Compromised Persons
Changing geography
• Drug resistant
Pneumococcus
• ESBLs with
cephalosporin UTI
prophylaxis
• MRSA skin infections
• MDR TB
• Resistant STDs
Enterococcus in Surface Waters
Number of Isolates
700
600
500
400
300
200
100
0
Negative
Positive
VRE
Des Moines River Watershed
6408 Square Miles
14 towns of > 5000
Row Crops and CAFO
Site 40 is Des Moines, Iowa
The Associated Press April 11, 2012, 5:25PM
FDA wants limits on antibiotics given to animals
By MATTHEW PERRONE
WASHINGTON
The Food and Drug Administration called on drug companies Wednesday to help limit the
use of antibiotics in farm animals, a decades-old practice that scientists say has contributed
to a surge in dangerous, drug-resistant bacteria….
…The FDA has struggled for decades with how to tackle the problem because the powerful
agriculture industry argues the drugs are a key part of modern meat production….
…Under the new FDA guidelines, the agency recommends antibiotics be used "judiciously,"
or only when necessary to keep animals healthy. The agency also wants to require a
veterinarian to prescribe the drugs. They can currently be purchased over-the-counter by
farmers….
The draft recommendations by the FDA are not binding, …
Acquisition of Antimicrobial Resistant Organisms
•
•
•
•
Confined Patients
Community Populations
Compromised Persons
Changing geography
• Prior antibiotic therapy
• Immune compromise
• Constitutional
compromise, hydration,
trauma, surgery
• Cancer
• Diabetes
• Etc
Incidence of ARO acquisition after Abx Tx was higher in
compromised pts than among overall pt population
• Relevant groups
were:
–
–
–
–
–
–
–
–
Dialysis
DM
ICU
Cirrhosis
Renal failure
Cancer
Age > 70
HIV
Fold Greater than non-compromised
Carbapenems
Piperacillin-tazobactam
Macrolides
Glcopepetides
Quinolones
Broad Spectrum cephalosporins
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
Tancrelli , et al. Antimicrob Agents Chemother 2009; 53: 4264
Population Movement
• Population movement
has the potential of
carrying resistant
microorganisms to new
places and new peoples
•
•
•
•
•
• Non colonized persons
may go to locations
•
where resistant
•
organisms are prevalent
•
•
Millions (year)
Refugees
16
(‘07)
Asylum Seekers 0.65 (‘07)
Displaced
51
(’07)
Travel
924 (‘08)
Seasonal Migr. 2.4 (‘05)
Int’l. Students
2.1 (‘03)
Migrant Work
86
(‘05)
Trafficked
0.8
Domestic Air Arr. 900 (‘07)
MacPherson et al, Emerging Infectious Disease 2009; 15:1727
Perspective:
Penicillin – “the first shall be last”
Colonization:
Contemporary concepts
Where it all begins, Where it stops
Cataloging the organisms of concern
The Pipeline is not the answer
Conceptualizing and Implementing
Antibiotic Stewardship
Brief summary of concerning
organisms
• Organisms intrinsically resistant
• One of the significant goals is reduction of
CDAD in hospitals and long term care
• Organisms with acquired and / or
transferrable resistance
• Multidrug resistant organisms
Concerning Organisms
• MRSA- methicillin/oxacillin-resistant Staphylococcus
aureus
• VRE - vanomycin-resistant enterococci
• ESBLs - extended-spectrum beta lactamases (resistant
to cephalosporins and monobactams)
• PRSP - penicillin-resistant Streptococcus pneumoniae
• GISA - glycopeptide-intermediate Staphylococcus
aureus
• VISA - vancomycin-intermediate Staphylococcus aureus
• VSRA - vancomycin-resistant Staphylococcus aureus
(not yet found in nature, but it is believed it will
emerge or evolve from VISA), and
• MDR-TB - multidrug-resistant tuberculosis.
Perspective:
Penicillin – “the first shall be last”
Colonization:
Contemporary concepts
Where it all begins, Where it stops
Cataloging the organisms of concern
The Pipeline is not the answer
Conceptualizing and Implementing
Antibiotic Stewardship
Antibiotic Resistance?
Just develop new
products!
This figure from a “Commentary” by Cooper and Shales, Nature 472:32, 2011
What is the pipeline?
•
•
•
•
•
•
•
•
Drug Discovery
Preclinical (in vitro and in vivo investigation)
Phase 0 Clinical (IND enabling research)
Phase 1 Safety, Dose Ranging
Phase 2 Safety, Efficacy, PK, PD
Phase 3 Clinical Efficacy, Safety – per indication
NDA
Marketing and Phase 4 monitoring
Fix the antibiotics pipeline…
• “Only 4 new classes of antibiotics have been
launched in the past 40 years”
• “Phase III clinical trials for a single disease
indication cost about $70 million”
• Investment capital is not attracted to drugs
that are used mainly for short courses
• The possibility of resistance development
means that new antibiotics may be short-lived
anyway
MA Cooper and D Shales, Nature 34, April 7, 2011
Perspective:
Penicillin – “the first shall be last”
Colonization:
Contemporary concepts
Where it all begins, Where it stops
Cataloging the organisms of concern
The Pipeline is not the answer
Conceptualizing and Implementing
Antibiotic Stewardship
Concept
• Antimicrobial resistance is driven by drug use
• Therefore less drug use will result in less
resistance
• Antibiotics are powerful resources so wholesale
abandonment is not an option
• Since 50% of use is considered ineffective or
irrational, antibiotic stewardship is a program for
appropriate use across institutions and specialties
Individual approach to
antibiotic stewardship
• Logical, evidence based, as specific as possible
with attention to local resistance issues, and
collaboration of the patient
• When ordering: include indication, dose,
discontinuation
• When patients are transferred antibiotic
treatments may be continued unnecessarily
12 Step Program for Institutional
Stewardship of Antibiotic Use
• Prevent Infections
1. Vaccination –
even antiviral
vaccination can lessen
the tendency to
antibiotic use
2. Get the catheters out
12 Step Program for Institutional
Stewardship of Antibiotic Use
• Diagnose and
Treat Effectively
3. Use appropriate
methods for
diagnosis
4. Target the pathogen
12 Step Program for Institutional
Stewardship of Antibiotic Use
• Use Antimicrobials
Wisely
5. Access the experts
6. Practice antimicrobial
control
7. Use local data
8. Treat infection and not
colonization
9. Know when to say
“no”
10. Stop treatment
12 Step Program for Institutional
Stewardship of Antibiotic Use
• Prevent
Transmission
11. Practice Infection
Control
12. Practice Hand Hygiene