Antibiotics
Past, Present and Future
Jay King
Ortho-McNeil
A Division of Johnson & Johnson
DISCLAIMER
Things aren’t so bad?
Or Are They?
“Past, Present and Future”….
Or a more appropriate title…..
“The Good, Bad and the Ugly”
Antibiotic Quotes
• In 1969 the U.S. Surgeon General, William H.
Stewart declared “It’s time to close the book
on infectious disease and declare the war
against pestilence won.”[1]
• August 3, 2002, Infectious Disease Specialist
Dr. Andrew Simor stated “We’re not at the
point where all antibiotics are useless, that’s
overstating it…..But there’s no question we
have a problem with increasing bacterial
resistance to current antibiotics.”[2]
•
•
[1] The office of the Public Health Service Historian. Frequently Asked Questions. US Public Health Service. Office of the
librarian 2006
[2] The Toronto Star, August 3, 2002, Section A, Page 1
Quote From Nobel Prize Winner
Joshua Lederberg
• “We are running out of bullets for
dealing with a number of bacterial
infections. Patients are dying because
we no longer in many cases have
antibiotics that work.”
Source: Senate Hatch Provision Speech, May 7th, 2007
Objectives
• Review the History & Milestones of
Antibiotics
• Show Resistance Trends and Impact
• Share the Challenges at Hand
• Antibiotic Stewardship Programs
• IDSA Wish-list
• What’s Coming?????
The History of Antibiotics
Landmark Dates
Antibiotic Landmark Dates
• 1920’s-50’s: Scientists harness the power of
living organisms to fight bacteria, ushering in
the era of antibiotics
• 1928: Scottish bacteriologist Alexander
Fleming, accidentally discovers that a mold
juice he names penicillin can kill
staphylococcus bacteria.
Source: CQ Researcher online: compiled by Denver Post Librarian Barry Osborne
Landmarks continued…..
• 1940: Oxford University pathologist
Howard Florey isolates pure penicillin
and demonstrates how it can cure a
wide range of pathogens, including
strep infections, gonorrhea and syphilis.
• 1943: Penicillin becomes the first
antibiotic to be put in widespread use.
Source: CQ Researcher online: compiled by Denver Post Librarian Barry Osborne
Landmarks continued….
• 1944: Russian-born microbiologist Selman
Waksman, working in the United States with
soil microbiologist Albert Schatz, discovers
streptomycin, a powerful antibiotic that
proves effective against tuberculosis.
• 1967: The first penicillin-resistant
pneumonococcal bacteria are reported in New
Guinea.
Source: CQ Researcher online: compiled by Denver Post Librarian Barry Osborne
Landmarks continued
• 1968: Drug-resistant Shigella diarrhea
kills 12,500 people in Guatemala.
• 1970-72: Penicillin-resistant gonorrhea
spreads around the world, transmitted
in part by U.S. servicemen, who
contract the disease from prostitutes in
Southeast Asia.
Source: CQ Researcher online: compiled by Denver Post Librarian Barry Osborne
Landmarks continued
• 1976: Several weeks after attending an
American Legion convention in
Philadelphia, 34 people die from a
mysterious form of pneumonia that
thwarts available treatments and comes
to be known as Legionnaires’ disease.
Source: CQ Researcher online: compiled by Denver Post Librarian Barry Osborne
Landmarks continued
• 1980s-90s: The public-health effects of drugresistant bacteria become clear, prompting
new concerns about infectious disease.
• 1986: The U.S. Food & Drug Admin., the
Center for Disease Control and Prevention,
and the Dept. of Agriculture establish a
national anti-microbial-resistance monitoring
system to track food-borne microbes.
Source: CQ Researcher online: compiled by Denver Post Librarian Barry Osborne
Landmarks continued
• 1988-95: Studies in Finland, the
Netherlands and other European
Countries find increasing drug
resistance in farm animals. Many of the
livestock are fed antibiotics as growthpromoters.
Source: CQ Researcher online: compiled by Denver Post Librarian Barry Osborne
Landmarks continued
• 1990: Puppeteer Jim Henson, creator of the
Muppets, dies of toxic-shock syndrome
induced by an aggressive strain of
streptococcus that acts too quickly for
antibiotics to work.
• 1992: The federal government is spending
just $55,000 a year monitoring drug
resistance.
Source: CQ Researcher online: compiled by Denver Post Librarian Barry Osborne
Landmarks continued
• 1995: A form of staph infection that is
resistant to methicillin results in almost a halfbillion dollars in direct medical costs and
claims 1,409 lives in New York City Hospitals.
• 1996: Japanese bacterial geneticists detect
the world’s first staph infection capable of
resisting the powerful antibiotic, vancomycin.
Source: CQ Researcher online: compiled by Denver Post Librarian Barry Osborne
Landmarks continued
• 1997: Health officials report the percentage
of antibiotic-resistant cases has surged from
2% in 1991 to 43% in 1997.
• 1998: The Institute of Medicine contends
that overuse of antibiotics has brought about
widespread drug resistance, estimating that
as many as half of the prescriptions for the
drugs given each year are unnecessary. The
U.S. Centers for Disease and Prevention
spends more than $11 million a year
monitoring drug resistance.
Source: CQ Researcher online: compiled by Denver Post Librarian Barry Osborne
Resistance
Antimicrobial resistance is
common, is increasing, and
has a major impact on
mortality, healthcare costs,
and disease severity.
Wanna Be A Superbug??????
Bacteria Facts
• There are 5-10 times more microbes living on
and in every human being than there are
human cells in our body.
• Bacteria exist in large numbers miles deep in
the midst of solid rock in the earth’s crust.
• Microbes comprise fully 60% of the biomass
on the planet (90% if cellulose is excluded
from the calculation) despite their submicron
size.
Spellberg S, et al. CID 2008:46 (15 January)
Microbe Resilience
• Microbes can exist despite:
– Extremes of boiling or freezing temperatures
– Pressures sufficient to crush virtually any humanmade submersible
– Extreme salinity
– Zero oxygen content
– Presence or absence of sunlight
Spellberg S, et al. CID 2008:46 (15 January)
So, are we at war with bacteria?
It’s important to remember, humans
did not invent antibiotics……
We only discovered them!!!
Current Resistance Trends
MRSA Facts
• The prevalence of MRSA in intensive care units went
from 36% in 1992 to 62% in 2002.[3]
• The most recent National Nosocomial Infections
Surveillance Report noted that rates of infection with
S. Aureus resistant to methicillin, oxacillin, or nafcillin
was approximately 60% in 2003.[4]
• In 2006, the prevalence of MRSA in ER patients with
skin and soft tissue infection was 59% overall. [5]
[3] McDonald LC. CID. 2006;42(suppl 2): S65-S71
[4] (NNIS) System Report, data summary from Jan. 1992 through June 2004, issued
Oct. 2004. Am J Infect Control. 2004; 32: 470-485
[5] Moran GJ, et al. N Engl J Med. 2006; 355: 666-674
Hospital Antimicrobial Resistant Facts
• About 70% of hospital-acquired bacterial
infections are resistant to at least one
antimicrobial agent.
• Treating these antibiotic resistant infections
can require longer lengths of stay in the
hospital and thus greater costs of treatment.
1
•
1
IDSA. Bad bugs, no drugs. 2004
1
Gram Negative Resistance Facts
• In 2003, gram negative bacilli in the
ICU were associated with:[6]
– 71.1%
– 65.2%
– 33.2%
– 23.8%
–
of
of
of
of
urinary tract infections
pneumonia episodes
surgical site infections
bloodstream infections
[6] Gaynes R et al. CID. 2005; 41: 848-854
Pseudomonas Resistant Facts
• Pseudomonas Aeruginosa is responsible for
10% of all hospital acquired infections.[7]
• In 2003, resistance among pseudomonas
isolates recovered from the ICU to 3rd
generation cephalosporins and quinolones
was approximately 30% and was 20% to
carbapenems.[8]
•
•
[7] Aloush V, et al. Antimicrobial Agents Chemo. 2006; 50 (1) :43-48
[8] McDonald L.C. CID. 2006; 42 (suppl 2) : S65-S71
5-Year E coli % Resistance Trend
from TRUST 2003 to 2007
Antimicrobial 2003 2004 2005 2006 2007 5-year
%
N=91
N=143 N=172
N=760 N=1303
Agent
5
5
4
Incr
Ampicillin
34.6
39.7
41.0
44.7
48.3
13.7
Trimeth/sulfa 16.8
19.3
19.5
20.4
26.3
9.5
Ciprofloxacin
9.1
9.5
9.8
14.8
19.6
10.5
Levofloxacin
9.1
9.5
9.4
14.0
18.9
9.8
Gentamicin
4.0
4.9
4.9
6.8
7.9
3.9
In vitro activity does not necessarily correlate with clinical results.
Data on file, Ortho-McNeil-Janssen Pharmaceuticals, Inc.
Ciprofloxacin & Levofloxacin
GU Scripts
Ciprofloxacin
Levofloxacin
6
ciprofloxacin
2005-2007
incr of 33%
5.2
Introduction of
generic ciprofloxacin
5
4.6
(1.3M scripts)
TRXs (MM)
3.9
4
3.4
3.4
3
2
1.5
1.6
1.8
1.8
1.7
1
0
Jan-Jun 2003
Jan-Jun 2004 Jan-Jun 2005 Jan-Jun 2006 Jan-Jun 2007
Source: SDI/ IMS Total GU TRxs
So How Do We Combat
Resistance?
New Antibiotic Development
&
Appropriate Antibiotic Usage
New Drug Research and
Development
An Aggressive R&D Program Initiated
Today Would Likely Require 10 or More
Years and an Investment of $800
Million to $1.7 Billion to Bring a New
Drug to Market. [9]
[9]Copyright IDSA 2007, info@idsociety.org
Molecule to Medicine
mms://janbebemedia.eu.jnj.com/Proje
ct/LR/2007/JJPRD/PRD0002T0531Weg
Molec_E.wmv
I Wanna New Drug!!!!!
Challenges for Antibiotic Research
and Development
• Because antibiotics work so well and so fast,
in most cases they simply don’t have as large
a market as drugs that treat chronic, longterm conditions or lifestyle issues. [10]
• The development of resistant strains of
bacteria limits the long-term potential for an
antibiotic. [10]
•
[10] Copyright IDSA 2007, info@idsociety.org
Challenges Continued
• Infectious disease experts often suggest
restrictions on the use of new antibiotics in
order to preserve the effectiveness of these
drugs for those patients who need them
most. Although sensible from a public health
perspective, such restrictions reduce the
incentive for companies to develop new
antibiotics. [11]
•
[11]Copyright IDSA 2007, info@idsociety.org
Challenges Continued
• Drugs to treat infectious diseases require an
additional “burden of proof” in the drug
approval process.
– Clinical trials for each indication
– Large # of patients to ensure safety and efficacy
– Large # of patients to document drug’s effectiveness against
specific bacterial pathogens
– No rapid diagnostic test to identify eligible patients with
resistant pathogens[12]
•
[12]Copyright IDSA 2007, info@idsociety.org
Results of Challenges
• A recent analysis published in Clinical
Infectious Disease (CID) found only five
antibiotics in the R&D pipeline out of more
than 506 drugs in development. By
comparison, pharmaceutical companies were
developing 67 new drugs for cancer, 33 for
inflammation and pain, 34 for
metabolic/endocrine disorders, and 32 for
pulmonary disease.[13]
• [13]Copyright IDSA 2007, info@idsociety.org
More Results
• The CID analysis found that FDA
approvals of new antibiotics declined
56% during the past 20 years(19982002 versus 1983-1987)
• In 2002, among 89 new medicines
emerging on the market, none was an
antibiotic.[14]
[14]Copyright IDSA 2007, info@idsociety.org
Companies That Appear To Be Withdrawing From
the Antibiotic R&D Market[15]
•
•
•
•
•
•
•
Aventis
Abbott Laboratories
Bristol-Myers Squibb
Eli Lilly and Co.
Proctor & Gamble
Roche
Wyeth
•
[15]Copyright IDSA 2007, info@idsociety.org
IDSA “Wish-list”
• A set of 12 strategies to address antimicrobial
resistant infections.
• The wish list takes a holistic approach to the
problem by recognizing that each of us,
including physicians, patients, antibiotic
manufacturers, personnel at hospitals and
other health care facilities, and others, must
act as good partners in keeping antibiotics
available and effective for the long term.[16]
•
[16]Spellberg, B., et al, CID, 2008:46 pg 6
Wish-list Proposals Are As Follows:
• 1) The creation of a Federal Office of
Antimicrobial Resistance in the Dept of
health and human Services to
coordinate and fund the work of the
Interagency Task Force to further
strengthen and implement the domestic
Action Plan, as well as to develop an
international action plan.
Wish-list Cont.
• 2) The creation of a public health
advisory board comprised of experts,
including specialists in infectious
diseases, hospital and communitybased physicians, public health
officers,and veterinary and research
specialists, to recommend ways to
strengthen the federal action plan. [16]
[16]Spellberg, B., Et al, CID, 2008:46 pg 6
Wish-list Cont.
• 3) The establishment of a federal
strategic research plan on antimicrobial
resistance that will focus on basic,
clinical, translational, epidemiological,
and intervention research.
[16]Spellberg, B., et al, CID, 2008:46 pg 6
Wish-list Continued
• 4) The creation of an Antimicrobial
Resistance Clinical Research and Public
Health Network (at least 10 sites across the
U.S.) to track and confirm, in near real time,
the emergence of antibiotic-resistant
pathogens, to conduct research, and to
enhance our capacity to prevent, control, and
treat infections due to antibiotic-resistant
organisms. [16]
[16]Spellberg, B., et al, CID, 2008:46 pg 6
Wish-list Continued
• 5) The collection of relevant
antimicrobial consumption data,
including antibiotic human and animal
antibiotic use data and available
prescribing data.
• 6) Strengthened surveillance programs
to monitor and track resistance
patterns. [16]
[16]Spellberg, B., et al, CID, 2008:46 pg 6
Wish-list Continued
• 7) A requirement that pharmaceutical
manufacturers submit to the FDA, as a part of
a new drug application, a resistance impact
statement that predicts how approval and use
of the antibiotic may impact the development
of resistance, as well as a management plan
that aims to slow the development of
resistance associated with the drug’s use.[16]
[16]Spellberg, B., et al, CID, 2008:46 pg 6
Wish-list Continued
• 8) Sufficient federal funding to implement
the federal Action Plan, including for antibiotic
stewardship programs to limit the spread of
resistance.
• 9) The establishment and periodic updates
by the FDA of antibiotic susceptibility
breakpoints for microorganisms based on
expert input, to assist physicians in using
antibiotics wisely. [16]
[16]Spellberg, B., et al, CID, 2008:46 pg 6
Wish-list Continued
• 10) A reassessment and strengthening of
FDA’s regulatory authority relating to the use
of antibiotics in food-producing animals.
• 11) More appropriately regulate the use of
antibiotics in agriculture, including phasing
out the use of antibiotics for growth
promotion in food animals. [16]
[16]Spellberg, B., et al, CID, 2008:46 pg 6
Final Wish on Wish-list
• 12) A requirement that the US GAO
audit the success of the aforementioned
measures in completing their stated
aims. [16]
[16]Spellberg, B., et al, CID, 2008:46 pg 6
Appropriate Antibiotic Use
The 4 D’s of Appropriate Antibiotic
Usage:
•
•
•
•
Drug
Dose
Duration
De-escalation
Antimicrobial Stewardship
Programs
An initiative to promote responsible
use of antibiotic resources
What Is the Goal of an Antimicrobial
Stewardship Program?
• The goal of antimicrobial stewardship is to
select the appropriate antibiotic, prescribe it
at the right dose and the optimal duration, so
that it provides the patient with the best
possible clinical outcome while minimizing
adverse events, the selection of pathogenic
organisms, and the development of
resistance. [18] [19]
•
•
[18] Dellit TH, et al. CID. 2007; 44: 159-177
[19] Owens RC, Ambrose PG. Diagn Microbiol Infect Dis. 2007; 57 (3 Suppl) :S77-S83
Antimicrobial Stewardship Team
Consists of:
•
•
•
•
Hospital Administrators
Staff Physicians
Infection Control Staff
Pharmacy Staff
Potential Recommendations of a
Stewardship Team
•
•
•
•
•
Prospective audit with intervention and feedback
Formulary restriction and preauthorization
Development of guidelines and clinical pathways
Antimicrobial order forms
De-escalation therapy, which may include initial
combination therapy
• Dose optimization
• Parenteral to oral oral conversion as soon as possible
• Computer surveillance and decision support [18]
[18] Dellit TH, et al. CID. 2007; 44: 159-177
Is There Any Help Coming?
New and Developing Antibiotics
• Doripenem—10/07-FDA approved Broad
spectrum carbapenem with pseudomonas
activity
• Dalbavancin—12/07- Approvable letter from
FDA--Lipoglycopeptide with MRSA activity
• On February 11, 2008, Targanta submitted a
New Drug Application (NDA) to the US FDA
seeking approval of oritavancin—A semi
synthetic glycopeptide antibiotic being
developed for the treatment of serious Grampositive infections
Antibiotics in Development
• Johnson and Johnson expects approval of
Ceftobiprole in April 2008—a broad spectrum
cephalosporin with MRSA activity
• January, 2008--Arpida gets FDA go-ahead for phase
II efficacy trial with oral iclaprim as step-down from
IV vancomycin in cSSSI
• January,2008--Trius Therapeutics initiates US Phase
I with TR-701, an IV/Oral oxazolidinone
• Forest Laboratories and Novexel announce a license
agreement for NXL 104, a Broad-Spectrum Beta
Lactamase Inhibitor to combine with Ceftaroline
• Merck is involved in initial research on
Platensimycin—a new class of antibiotic for Gram
positive infection including MRSA—A decade away
Carlos Don’s Story
Health Professionals Can Impact
Patients
Other clinicians
Optimize patient evaluation
Adopt judicious antibiotic
prescribing practices
Vaccinate patients
Optimize consultations with
other clinicians
Use infection control measures
Educate others about judicious
use of antibiotics
Conclusion