Antibiotic Resistance and the

Antibiotic Crisis

Daniel Z. Uslan, MD Director, Antimicrobial Stewardship Program

Assistant Clinical Professor Division of Infectious Diseases, UCLA

Learning Objectives

Understand the present crisis of resistant microorganisms and declining antibiotic development

Identify the reasons for physician misuse and overuse of antibiotics

Describe antibiotic stewardship programs and understand their role in decreasing utilization

Systematically apply specific strategies to improve antibiotic utilization

Cite cultural considerations in the prevalence of this topic

Cultural Considerations

CA Assembly Bill 1995 requires each CME activity to have a component on Cultural Diversity

No studies on antibiotic prescribing differences or resistance among different races/ethnicities

• In December 1942, a 4 yo girl in excellent health developed facial cellulitis after trauma

• Spread relentlessly, fever to 104 F, could not sleep because her face and neck so swollen she could not swallow her own saliva

• Began gasping for breath

Herrell ’43 Proc Staff Meetings Mayo Clinic 18:65-76

The“Dark Ages”

On arrival to the hospital

After 14 days of penicillin

“Moribund”

“dead within 2 days”

Totally fine…  for >65 years

“For most of the infectious diseases on the wards of Boston City Hospital in 1937, there was nothing that could be done beyond bed rest and good nursing care. Then came the explosive news of sulfanilamide, and the start of the real revolution in medicine.”

Why Is This Important?

Lewis Thomas. Notes of a Medicine Watcher. ‘83. Viking Press

Lewis Thomas, MD • Albert Lasker Award winner • Member of the National Academies of Science

• National Book Award

Why Is This Important? Lewis Thomas. Notes of a Medicine Watcher. ‘83. Viking Press

“I remember the astonishment when the first cases of pneumococcal and streptococcal septicemia were treated in Boston in 1937. The phenomenon was almost beyond belief. Here were moribund patients, who would surely have died  without  treatment,  improving…within  a  matter  of  hours…and  feeling  entirely  well  within  the  next  day…we became convinced, overnight, that nothing lay beyond reach for the future. Medicine was off and running.”

The Power of Antibiotics

Disease Pre-Antibiotic Death Rate

Death Rate with Antibiotics

Change in Death Rate

Community

Pneumonia1

35% 10% -25%

Hospital

Pneumonia2

60% 30% -30%

Endocarditis3 100% 25% -75%

Meningitis4 80% 20% -60%

Cellulitis5 11% <0.5% -10%

By comparison, treatment of acute MI with aspirin6 -3%

1IDSA  Position  Paper  ‘08  Clin  Infect  Dis  47(S3):S249-65;  2IDSA/ACCP/ATS/SCCM  Position  Paper  ‘10  Clin  Infect  Dis  In  Press;  3Kerr  AJ.

Subacute Bacterial Endocarditis. Springfield IL: Charles C. Thomas, 1955 & Lancet 1935 226:383-4;  4Lancet  ‘38  231:733-4 & Waring et  al.  ‘48  Am J Med 5:402-18;  5Spellberg  et  al.  ‘09  Clin  Infect  Dis  49:383-91  &  Madsen  ‘73  Infection  1:76-81;  6‘88  Lancet  2:349-60

Why Is This Important? “…with  today’s [antibiotics] it is possible to place in the hands of a barefoot, nonliterate villager more real power to affect the outcome  of  a…critically  ill  [patient]…than  could  have  been exerted by the most highly trained urban physician of 25 years ago.” (Dr. Walsh McDermott 1960 Science 131:197-205)

Walsh McDermott, MD Cornell University • 1st President of Medical Board of National Academy of Sciences (precursor to IOM)

• Albert Lasker Award winner for early work on isoniazid

In  just  75  years… RIP Antibiotics: 1937 - 2012

Antibiotic-Resistance Is Skyrocketing

(CDC Data)

% o

f iso

late

s

0

200

400

600

800

1000

1200

1993 1995 1997 1999 2001 2003 2005Rat

e pe

r 100

,000

hos

pita

l dis

char

ges

US hospital discharges with diagnosis of infection with drug-resistant microorganisms

1993-2005

Courtesy John Rex 1%

0.6%

0.3%

1993-2005: A dramatic increase

Data from US Healthcare Cost and Utilization Network

2010-02-23 IOM Countermeasures, Big Pharma Commercial Perspectives - Rex

No New Classes to Treat Gram Negative Bacilli For 4 Decades

Courtesy J.G. Bartlett

“For Gram positives, we need better drugs. For Gram negatives, we need ANY drugs.” John Bartlett, MD

Nov, 2006

Geographical distribution of extreme-drug resistant KPC Klebsiella bacteria

Current

Geographical distribution of extreme-drug resistant KPC Klebsiella bacteria

• In 2010, reports of new resistant mechanism spread from India to UK/US

•All strains resistant to all antibiotics except tigecycline or colistin

• 10% strains resistant to both of those drugs also—truly pan-resistant

•This is our worst nightmare

Kumarasamy ’10 Lancet Infectious Diseases 10:597-602; MMWR ’10 59:750

NDM-1 E. coli & Klebsiella

Pan Resistant Superbugs

“For these infections, we're back to dancing around a bubbling cauldron while rubbing two chicken bones together.”

--Brad Spellberg, MD Page A1 (front page) Quote of the Day

11/6/10, New York Times, report on antibiotic resistant infections

21

Health Care Costs of Resistance

•Resistant infections prolong length of hospital stay by 24% and increase costs by 29% vs. susceptible infections (Maudlin et al. AAC ’10 54:109-115)

•Cost to US of antibiotic resistance is 8 million additional hospital days and $21-34 billion/yr

(Roberts et al. CID ’09 49:1175-84; & PRN Newswire “Antibiotic-Resistant Infections Cost the U.S. Healthcare System in Excess of $20 Billion Annually” 10-19-09)

2 million people acquire healthcare-associated infections

per year

100,000 people die as a result More than AIDS, breast cancer, traffic accidents combined

Microbes vs. Humans

Microbes Humans Factor

Number on Earth 5x1031 6x109 1022

Mass (metric tons) 5x1016 3x108 108

Generation Time 30 min 30 yr 5x105

Time on Earth (yrs) 3.5x109 4x106 103

Microbiology in the 21st century, ASM, 2004; Spellberg et al 2008 Clin Infect Dis

Microbes vs. Humans

Genetic Promiscuity Diversity/Adaptability

Microbes Cross-phylum

Humans* Intra-species

*genus/species Homo sapiens, family Hominidae, order Primate, class Mammalia, phylum Chordata

Microbes vs. Humans

Equivalent promiscuity would require capability to exchange DNA with:

•chimpanzee (family Hominidae)

•orangutan (order Primate)

•grizzly bear / tiger / walrus / killer whale (class Mammalia)

•falcon / frog / crocodile (phylum Chordata)

Pretty cool

Microbes have been creating

and defeating antibiotics for

20 million times longer than

Homo sapiens have even

known antibiotics existed.

“The future of humanity and microbes will likely evolve as…episodes  of  our  wits  versus  their genes.”

Nobel Laureate Joshua Lederberg Science 2000 288:287-93

How Do We Combat Resistance? Two Options

1. New Antibiotics

New Drug Research and Development

A  short  section…

New Antibacterial Agents Approved 1983-2012

0

2

4

6

8

10

12

14

16

18

1983-1987 1988-1992 1993-1997 1998-2002 2003-2007 2008-2012

Timeline for Development of a New Antibiotic

In  contrast…

67 new drugs for cancer

33 for inflammation and pain

34 for metabolic/endocrine disorders

32 for pulmonary disease