Antibiotics Past, Present and Future Jay King Ortho-McNeil A Division of Johnson & Johnson

AntibioticsPast, Present and Future

Jay KingOrtho-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.


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.


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.


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.


Landmarks continued• 1980s-90s: The public-health effects of

drug-resistant 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.


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 growth-promoters.


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.


Landmarks continued• 1995: A form of staph infection that is

resistant to methicillin results in almost a half-billion 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.


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.


ResistanceAntimicrobial 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

human-made 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.

• IDSA. Bad bugs, no drugs. 2004

1

1

1

Gram Negative Resistance Facts

• In 2003, gram negative bacilli in the ICU were associated with:[6]– 71.1% of urinary tract infections– 65.2% of pneumonia episodes– 33.2% of surgical site infections– 23.8% of 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

In vitro activity does not necessarily correlate with clinical results.

Data on file, Ortho-McNeil-Janssen Pharmaceuticals, Inc.

AntimicrobialAgent

2003N=91

5

2004N=760

2005N=1303

2006N=143

5

2007N=172

4

5-year%

Incr

Ampicillin

Trimeth/sulfa

Ciprofloxacin

Levofloxacin

Gentamicin

34.6

16.8

9.1

9.1

4.0

39.7

19.3

9.5

9.5

4.9

41.0

19.5

9.8

9.4

4.9

44.7

20.4

14.8

14.0

6.8

48.3

26.3

19.6

18.9

7.9

13.7

9.5

10.5

9.8

3.9

Ciprofloxacin & Levofloxacin GU Scripts

3.4

1.5

3.4

1.6

3.9

1.8

4.6

1.8

5.2

1.7

0

1

2

3

4

5

6

TRX

s (M

M)

Jan-Jun 2003 Jan-Jun 2004 Jan-Jun 2005 Jan-Jun 2006 Jan-Jun 2007

Ciprofloxacin Levofloxacin

Source: SDI/ IMS Total GU TRxs

ciprofloxacin2005-2007 incr of 33%

(1.3M scripts)

Introduction of generic ciprofloxacin

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, [email protected]

Molecule to Medicine

mms://janbebemedia.eu.jnj.com/Project/LR/2007/JJPRD/

PRD0002T0531WegMolec_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, long-term 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, [email protected]

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, [email protected]

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]


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]


More Results

• The CID analysis found that FDA approvals of new antibiotics declined 56% during the past 20 years(1998-2002 versus 1983-1987)

• In 2002, among 89 new medicines emerging on the market, none was an antibiotic.[14]

[14]Copyright IDSA 2007, [email protected]

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


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 community-based 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]


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]


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]


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]


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]


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]


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 Gram-positive 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

Optimize patient evaluation Adopt judicious antibioticprescribing practicesVaccinate patients

Optimize consultations with other cliniciansUse infection control measuresEducate others about judicious use of antibiotics

Conclusion

Documents

Antibiotics Past, Present and Future Jay King Ortho-McNeil A Division of Johnson & Johnson