who collaborating center for surveillance of antimicrobial resistance boston, usa antimicrobial...

WHO Collaborating Center for Surveillance of Antimicrobial ResistanceBoston, USA

Antimicrobial resistance – Biological basis and public health consequences

John Stelling, MD, MPHWHO Collaborating Centre for

Surveillance of Antimicrobial ResistanceBoston, USA


What is antimicrobial resistance?

• If a drug has no effect on a bacteria, the bacteria is Resistant to the compound

• Some resistance is ancient – intrinsic– E. coli and vancomycin– M. tuberculosis and penicillin

• A lot of it is new since 1930 – acquired– S. aureus and oxacillin– N. gonorrhoeae and penicillin


Our universe – an overview

Big Bang The Sun Earth Bacteria Humans

12 Billion 10 Billion 6 Billion 4 Billion

Organisms have been producing “antibiotics” for billions of years – on a tiny scale! Humans have been using antibiotics on massive scales for the past seven decades

Present

ASM, © David Phillips/Visuals Unlimited

Dinosaurs

“Antibiotics” Antibioticuse


pABA DHF THF

Folate Synthesis PLASMID

CHROMOSOME

Protein Synthesis

Gram Positive Bacteria Gram Negative Bacteria

Cell Wall Synthesis

RNA Synthesis

DNA Synthesis

CELL WALLCELL MEMBRANE BIOFILM

RIBOSOMES

OUTER MEMBRANE


How do susceptible bacteria become resistant?

• Mutation

• Acquisition of resistance genes

S

R

S

R

R

R

In most bacteria, these events are rare* – but critical!* But there are important exceptions – M. tuberculosis, Pseudomonas, Enterobacter


Why are resistant bacteria so common?

• Selection

• Spread


Leading bacterial pathogens in 1900

Streptococcus pneumoniae Corynebacterium diphtheriaeStreptococcus pyogenes Mycobacterium tuberculosisStaphylococcus aureus Haemophilus influenzaeEscherichia coli Neisseria meningitidisVibrio cholerae Neisseria gonorrhoeaeShigella species Treponema pallidumSalmonella typhi


Initial appearanceVancomycin-intermediate Staphylococcus aureus

Responses: confirmation, molecular characterization, diagnostic tools,active surveillance, notification of health care providers and generalpublic, review of treatment guidelines, development of new agents


SpreadStrep. pneumoniae: multi-resistant, virulent clones

Source: WHO Report WHO/CDS/BVI/95.7


Emergence in hospitalsVancomycin-Resistant Enterococci, USA

0

2

4

6

8

10

12

14

% R

esis

tant

1989 1990 1991 1992 1993 1994

Intensive care units non-intensive care units

Source: National Nosocomial Infections Surveillance System, CDC, USA


Emergence in the community Resistant E. coli in Healthy Children

0102030405060708090

100

% R

esis

tan

t

TetracyclineGentamicin Resistant to1 or more

drugs

Resistant to5 or more

drugs

United States

Venezuela

China

Source: Lester, NEJM 323:285-289


Emergence in outbreaksShigella sp. in Rwanda, Amp+TMP Resistant

0

20

40

60

80

100

83 84 84 86 87 88 89 90 91 92 93

S. dysenteriae type1

S. flexneri

S. sonnei

S. boydii anddysenteriae 2-10

Resistance in S. dysenteriae type 1 has been high for many years.Resistance in other species has been increasing in recent years.


0

5

10

15

20

1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994

2 antimicrobial drugs 3 antimicrobial drugs

Pig isolates

Emergence in animals and humansResistant Salmonella Typhimurium, Netherlands

0

5

10

15

20

1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994

Human isolates


The impact of 7 decades of antibiotic use and misuse on bacterial

populations

• Same pathogens as in 1930– BUT NOW WITH ACQUIRED RESISTANCE!!

• Plus many new species– Staph. epidermidis, Enterococcus, Pseudomonas, Klebsiella,

Acinetobacter, fungi, etc.– features:

• take advantage of changing societal demographics• take advantage of changes in health-care practice• intrinsic resistance to commonly used antimicrobials!!

The use of antibiotics has radically altered the microbial populations of the world and the epidemiology of infection


The impact of Antimicrobial resistance

• Consequences– morbidity and mortality– direct and indirect costs– transmission

• Antimicrobials are “societal” drugs. Antimicrobial use in one person affects us all


Antimicrobial resistance as an unusual public health threat

• A problem created by medical innovation– antimicrobial use by patients, health-care providers,

food-producers, industry drives resistance trends

• A problem of dependence– Antimicrobial resistance is NOT a disease. It’s a

characteristic of many organisms which cause a wide variety diseases.

– If we can prevent or treat disease in other ways, resistance would cease to be a public health menace.


Strategies for Containment of Antimicrobial resistance

John Stelling, MD, MPHWHO Collaborating Centre for

Surveillance of Antimicrobial ResistanceBoston, USA


• Target areas– Disease prevention and infection control– Access to antimicrobials– Appropriate use– Legislation and regulation– Surveillance– Focused research

• Target groups– patients and general community– hospitals, prescribers and dispensers– food animal industry– governments and health systems– international organizations– pharmaceutical and diagnostic industries– researchers

T h e M e d ic a l I m p a c t o f th e U s e o f A n t im ic r o b ia ls in F o o d A n im a ls

D iv is io n f o r E m e r g in g a n d o th e r C o m m u n ic a b le D is e a s e s S u rv e il la n c e a n d C o n tr o l

W o r ld H e a lth O r g a n iz a tio n

R e p o r t o f a W H O M e e t in g

B e r lin , G e r m a n y 1 3 -1 7 O c to b e r 1 9 9 7

W H O /E M C /Z O O /9 7 .4

D is t r . : G e n e r a l

E n g l ish o n ly

T h e M e d ic a l I m p a c t o f th e U s e o f A n t im ic r o b ia ls in F o o d A n im a ls

D iv is io n f o r E m e r g in g a n d o th e r C o m m u n ic a b le D is e a s e s S u rv e il la n c e a n d C o n tr o l

W o r ld H e a lth O r g a n iz a tio n

R e p o r t o f a W H O M e e t in g

B e r lin , G e r m a n y 1 3 -1 7 O c to b e r 1 9 9 7

W H O /E M C /Z O O /9 7 .4

D is t r . : G e n e r a l

E n g l ish o n ly


In using antimicrobials, we mustseek a balance:

• Increase appropriate use of antimicrobials– Ensure the provision of good quality therapy

to infected patients who needs antimicrobials: standard treatment guidelines, drug access, drug quality

• Decrease inappropriate use of antimicrobials– Through education, policy, and regulation,

decrease the use of antimicrobials where there is no benefit to patients


Resistance emergence – Critical steps• New resistance

• Selection

• Spread

Mutations


Factors promoting resistance

• Selection pressure – antibiotic use– intensive use: intensive care units, new antibiotics– indiscriminate use: for nonbacterial diseases– incorrect use: inappropriate agent, dosing, compliance– use in animals and food production

• Spread– poor sanitation and overcrowding in the community– inadequate control of infections in health care facilities– international travel


-lactam consumption and TEM -lactamase resistance in M. (B.) catarrhalis from Finnish

children

0%

20%

40%

60%

80%

100%

1978 1983 1988 1993 1998

Year

Resis

tanc

e

50.9% increase

Nissinen et al. (1995), Clinical Infectious Diseases, 21: 1193-6

Total -lactam consumption

4

5

6

7

8

9

1978 1981 1984 1987 1990 1993

Year

DD

Ds/1

000 in

habitants

Penicillins Cephalosporins


AMR Containment Interventions:Approaches

• General– Disease prevention: improved hygiene, water

quality, nutrition– Disease therapy: decreasing inappropriate use

of antibiotics, development of new agents

• Disease-specific– Disease prevention: vaccination– Disease therapy: improved disease diagnosis,

standard treatment guidelines


Strategy 1: Reduce the need for antibiotics

• Disease prevention– use existing vaccines and develop new ones– improve nutrition, hygiene, and general health status

• New approaches for disease therapy– immune modulators, bacteriophages

• Evaluate the use of antibiotics in food production– decrease the use of antimicrobial growth promoters


Strategy 2: Improve the use of antibiotics

• Do not use antibiotics when they do not benefit the patient

– Educate health workers and patients• Ensure quality of drug supply

– Regulation and control of the quality of antimicrobials available on the market

• Use standard treatment guidelines adapted for local resistance issues

– use narrow-spectrum where appropriate– reserve highly effective drugs– regulate and monitor antimicrobial prescription– do susceptibility testing when possible– optimize surgical prophylaxis– improve patient compliance


0

5

10

15

20

25

30

35

FR GR LU PT IT BE SK HR PL IS IE ES FI BG CZ SI SE HU NO UK DK DE LV AT EE NL

DD

D p

er 1

000

inh

. per

day

Total Outpatient antibiotic use in 26 European countries in 2002


Consumption of the Fourth Generation Cephalosporins in Ambulatory Care in 26

European Countries in 2002

0.00

0.01

0.02

0.03

0.04

0.05

0.06

0.07

0.08

0.09

IT GR BG PL LV LU CZ BE AT FI SE SK DE NL FR PT ES HU HR IE SI IS UK DK EE NO

DD

D p

er 1

000

inh

. per

day

Cefpirome

Cefepime


Factors Influencing Drug Use

DRUG USE

Cultural Beliefs

Knowledge Deficits Unbiased

Information

RelationWith Peers

Authority &Supervision

Influence of Industry

Workload & Staffing

Infra-structure

Acquired Habits

Patient Demand

Interpersonal

Workplace

Workgroup

PersonalInformational


Penicillin consumption (1991-1996) and penicillin resistance (1988-2000) in S. pneumoniae from

Icelandic children

0%

5%

10%

15%

20%

25%

1988 1990 1992 1994 1996 1998 2000

Year

Resis

tanc

e

12.9% reduction

No intervention

Antimicrobial consumption

15

15.5

16

16.5

17

17.5

18

18.5

19

19.5

1991 1992 1993 1994 1995 1996

Year

DD

Ds/

1000

child

ren


Strategy 3: Decrease transmission

• Communities– improve sanitation and hygiene

• Health-care facilities– strengthen hospital infection control: hand-

washing, sterilization techniques, quality control, use of face masks


New Drug Development – 1995 -2005

• 80 FDA Drug Approvals for Anti-Infectives– 17 Antibacterials– 27 Anti-HIV– 23 Other antivirals– 7 Antifungals– 6 Antiparasitics


FDA Approved Antibacterials – 1995-2006

• 17 Antibacterials– 10 “New” Compounds – but no novel drug classes

• Ceftibuten, cefditoren• Moxifloxacin, trovafloxacin, gatifloxacin• Telithromycin, dirithromycin• Ticarcillin+clavulanic acid• Quinupristin/dalfopristin• Rifaximin

– 7 Reformulations of existing compounds• Clarithromycin, azithromycin• Metronidazole• Clindamycin• Cefazolin

• Two removed from market because of toxicity concerns

– Trovafloxacin, gatifloxacin


Disincentives to New Drug Development

• Because of resistance, anti-infectives lose efficacy over time

• Short courses of patient therapy• Tight restrictions on the use of new agents• Many competitors with very good safety

profiles• For “me too” drugs, resistance can emerge

rapidly


Conclusion

• Resistance is an unavoidable consequence of the use of anti-infective agents on diverse microbial populations

• Prudent antimicrobial use must thus aim to balance– the necessity of treating infected patients today with– the need for efficacious treatment options in

the future

who collaborating center for surveillance of antimicrobial resistance boston, usa antimicrobial...

Documents

usa slide

usa source

usa emergence

active surveillance

resistant bacteria

penicillin slide

enterobacter slide

selection spread slide