Microbial Colonization and New Resistant OrganismsBryan Larsen, PhD

Marian University College of Osteopathic Medicine

Perspective:Penicillin – “the first shall be last”Colonization:Contemporary conceptsWhere it all begins, Where it stops

Cataloging the organisms of concern

Conceptualizing and Implementing Antibiotic Stewardship

The Pipeline is not the answer

Ernst ChainD 1979

Howard FloreyD 1968

Norman HeatleyD 2004

Alexander FlemingD 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

Penicillin was so scarce and precious in the early days, that urine was processed to recover excreted drug

Perspective:Penicillin – “the first shall be last”Colonization:Contemporary conceptsWhere it all begins, Where it stops

Cataloging the organisms of concern

Conceptualizing and Implementing Antibiotic Stewardship

The Pipeline is not the answer

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 multi-site culture

• 47% entered the LTC facility with CIP-R• Time to acquisition (among non-colonized):– CIP-R 75.5 days– MRSA 126.6 days– CAZ-R 176 days– VRE 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

Carbapenem

Broad Spectrum cephalosporins

Quinolones

Glcopepetides

Macrolides

Piperacillin-tazobactam

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

Negative Positive VRE0

100

200

300

400

500

600

700

Number of Isolates

Des Moines River Watershed6408 Square Miles14 towns of > 5000Row Crops and CAFOSite 40 is Des Moines, Iowa

The Associated Press April 11, 2012, 5:25PM

FDA wants limits on antibiotics given to animals

By MATTHEW PERRONEWASHINGTON

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

Tancrelli , et al. Antimicrob Agents Chemother 2009; 53: 4264

Broad Spectrum cephalosporins

Quinolones

Glcopepetides

Macrolides

Piperacillin-tazobactam

Carbapenems

0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5

Fold Greater than non-compromised

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 conceptsWhere it all begins, Where it stops

Cataloging the organisms of concern

Conceptualizing and Implementing Antibiotic Stewardship

The Pipeline is not the answer

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 conceptsWhere it all begins, Where it stops

Cataloging the organisms of concern

Conceptualizing and Implementing Antibiotic Stewardship

The Pipeline is not the answer

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 conceptsWhere it all begins, Where it stops

Cataloging the organisms of concern

Conceptualizing and Implementing Antibiotic Stewardship

The Pipeline is not the answer

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 experts6. Practice antimicrobial

control7. Use local data8. Treat infection and not

colonization9. 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