Antibiotic Resistance and Hospital-Acquired Infection Prof ... · From “Battling bacterial evolution: The work of Carl Bergstrom” Understanding Evolution , University of California

Antibiotic Resistance and Hospital-Acquired Infection

Prof. Carl T. Bergstrom

The screen versions of these slides have full details of copyright and acknowledgements 1

1

Carl T. Bergstrom

Department of Biology

University of Washington

Antibiotic Resistance

and Hospital-Acquired Infection

2

Pennsyl vania Health Care

Cost Containment Council

In the first nine months of 2005, Pennsylvania hospitals reported:

13,711 hospital acquired infections

1,456 deaths

227,000 extra days of hospitalization

$2.3 billion in extra expenses

PHC4 Research Brief, March 29, 2006

3

Pennsyl vania Health Care

Cost Containment Council

Scaling these numbers up to the entire United States, we expect each year approximately:

450,000 hospital acquired infections

50,000 deaths

7,500,000 extra days of hospitalization

$75 billion in extra expenses




4

Antibiotic resistance

After decades of heavy antibiotic use in hospitals, many hospital-associated strains of bacteria

are resistant to multiple antibiotics

Infection with resistant strains:

Increases the probability of treatment f ailure

Extends the duration of hospital stay

Increases the mortality rate

Increases the economic cost of treatment

5

Staphylococcus aureusEnterococcus sp.

52 %

23 %

28 %

10 %

Resistance in the intensive care unitNational Nosocomial Infections Surveillance System Report, 2003

Klebsiella pneumoniae Pseudomonas aeruginosa

6

Playing catch-up ball

Linezolid?

MRSAVRE

Methicillin against

macrolide resistance

Vancomycin used

against MRSA

Linezolid

against VRE

0

Year

5

10

15

20

25

30

35

40

% Resistance




7

Combating antibiotic resistance

is a problem in applied evolution

8

How evolution works

Variation: dif f erent indiv iduals

hav e dif f erent traits

Heritability: of f spring tend to be

somewhat like their parents

Selection: indiv iduals with certain traits

surv iv e better or reproduce more

Time: successf ul v ariations accumulate ov er many generations

9From “Battling bacterial evolution: The work of Carl Bergstrom”Understanding Evolution, University of California

Natural selection, in a nutshell




10

1

Antibiotic-sensitive

Antibiotic-resistant

Dead

2 3

11

Transformational evolution

versus

Variational evolution

12

Transformational process

Variational process




13

1. Where does the variation come from?

2. What is the structure of selection?

3. How can we intervene?

1 2 3

14

Mutation

15

MutationMacrolide antibiotics block protein synthesis

by binding to bacterial ribosomes

From Hanson et al., (2002) Molecular Cell




16

Mutation

A single point mutation in the green binding region can prevent macrolide binding and confer resistance

Modified from Hanson et al., (2002) Molecular Cell

17

Mutation

Genome size: ~ 5 x 106 base pairsMutation rate: ~ 2 x 10-3 per genome

Population size: 1010 to 1011 per g fecal matter

A single gram of f ecal matter is likely to contain

a nov el point mutation conf erring macrolide-resistance!

18

The E. coli efflux pump AcrB

Edward Yu, Iowa StateMore complex mechanisms




19

“Nature makes penicillinI only found it”

- Alexander Fleming

Natural ecology of antibiotics

20

Soil microbes liv e in highly structured env ironments

with intense competition f or space and nutrients

Many microbes produce antibiotics to kill of f their competitors

Antibiotic producers must be resistant

to their own products;this generates a v ast reserv oir of resistance genes in bacterial populations

Natural ecology of antibiotics

21

Lateral gene transfer

ConjugationTransf ormationTransduction




22

Enterococcus

A. orientalis

Unknown

Van R,S

Van A,H,X

Lateral gene transfer

23

2




24

Most resistant strains are commensals




25

Extremely high rate of drug use

26

Hospital staff act as disease vectors

27

High rate of patient turnover

Community




28

Antibiotic use by non-hospitalized patients

leads to resistance in the community at large

Resistance in the community

29

Agricultural use

25 million pounds per year into animal feed

Union of Concerned Scientists, 2001

30

Agricultural use




31




1 32

32

Community

Hospital

A model of a hospital

Lipsitch, Bergstrom, and Levin (2000)

Proc. Nat. Acad. Sciences USA

33

Translate our model into equations

S: patients colonized with sensitiv e bacteria

R i: patients colonized with bacteria resistant to drug i

X: uncolonized patients

dS /dt = mµ+ βSX − (τ1 + τ 2 + γ +µ)S

dRi/dt = β(1− c)R

iX − (µ+ τ ~i + γ)Ri

dX /dt = (1− m)µ + (τ1 + τ 2 + γ)S + (τ2 + γ)R1

+(τ1 + γ )R2 − βSX − β(1− c)RiX −µX

Lipsitch, Bergstrom, and Levin (2000)





34

Things change fast

Non-specif ic controldoes appreciablyreduce resistance*

*When resistance is rare in the community

Formulary changescan rapidly eradicate resistant bacteria

We can study the dynamics using numerical solution

Infection control (70% transmission reduction)

Infection control + switch antibiotics

Time (days)

0

0.1

0.2

0.3

0.4

0.5

0.6

-30

Fraction resistant

-10 10 30 50 70

35

Odds ratios can be misleading

Patients treated with drug 2

have a higher chance

of carrying drug 1 resistance

Drug Y resistance

Treated with X

Untreated

Drug Y resistance

Drug X usage in hospital

Treated with X

Untreated

... but this is a poor measure of efficacy

In fact the net level

of drug 1 resistance drops as the use

of drug 2 increases

36

Antibiotic cycling

"The `crop rotation' theory of antibiotic use

[suggests] that if we routinely v ary

our ̀ go to' antibiotic in the ICU, we can minimize the emergence of resistance because the selectiv e pressure f or bacteria to dev elop resistance to a specif ic antibiotic would be reduced as organisms become exposed to continually v ary ing antimicrobials."

- M. Niederman (1997)

Am. J. Respir. Crit. Care Med.




37

Based on sound ecological principles:

Populations have a hard time tracking rapidly fluctuating environmental conditions

38Toltzis et al.(2002) Pediatrics

Cycling

gentamicinpiperacillin/tazobactamceftazidime

Control

gentamicinpiperacillin/tazobactamceftazidime

Cycling in a neonatal ICU

39

Clinical consequencesToltzis et al. (2002)

Infection Control Cycling

(n = 548} (n = 514)

Resistant colonization 7.7% 10.7%

Blood stream 40 42

Meningitis 4 1

Pneumonia 7 13

Urinary tract 7 9

Necrot. enterocolitis 8 7

No significant difference in nosocomial infection rate




40

Modelling the efficacy of cycling

Total resistant inf ections: R1 + R2

Baseline f or comparison: in each case, compare the outcomes under cy cling to an approximation of the status quo:

Mixing of the two drugs, in which at any giv en time half of the patients receiv e drug 1, the other half drug 2

Bergstrom, Lo, and Lipsitch (2004)


41

Total resistant infections

Cycling Mixing

Three month cycling period

Time in days

Fraction resistant

42

Total resistant infections by cycle length

Cycling Mixing

One year Three months Two weeks




43

Average total resistanceincreases with cycle period

Cycling Mixing

44

Why doesn'tcycling work?

Bed 1

TTime

2 3 4 5 6 7 8 9 10

45

Why doesn'tcycling work?

Time

Bed 1 2 3 4 5 6 7 8 9 10




46

Mixing creates more heterogeneous

environment than does cycling!

Bed 1

TTime

2 3 4 5 6 7 8 9 10

Time

Bed 1 2 3 4 5 6 7 8 9 10

47

US infectious disease mortalitythroughout the 20th century

Sulfonamides

Penicillin

1918 flu pandemic

HIV

Armstrong et al., 2001

48

Acknowledgements

Marc Lipsitch

Harvard School of Public Health

Bruce Levin

Emory University

Diane Genereux

University of Washington




49

Documents

Antibiotic Resistance and Hospital-Acquired Infection Prof ... · From “Battling bacterial evolution: The work of Carl Bergstrom” Understanding Evolution , University of California