Antimicrobial consumption and impact on resistance

Antimicrobial consumption and impact

on resistance

Dr. Rafael Cantón

Servicio de Microbiología. Hospital Universitario Ramón y Cajal

Associated Professor. Facultad de Farmacia. Universidad Complutense Madrid, Spain

5th ESCMID School of Clinical Microbiology

and Infectious Diseases

Santander, Spain

10-16 June, 2006

Antibiotic resistance

“Antibiotic resistance continues to plague antimicrobial chemotherapy of infectious diseases”

Keith. Poole. J Antimicrob Chemother 2005; 56: 20-51

“Evolution of bacteria towards resistance… …is unavoidable because it represents a particular aspect of the general evolution of bacteria that is unstoppable”

Patrice Courvalin. Emerg Infect Dis 2005; 11: 1507-

6

“Antibiotic resistance has resulted in a continuous need for new therapeutic alternatives”

Carl Erik Nord. Clin Microbiol Infect 2004;10 (Supp 4)

“There is a need to re-invigorate antimicrobial development, which has been downgraded by major pharmaceutical houses”

David Livermore. Lancet Infect Dis 2005; 5:450-59

1920 1930 1940 1950 1960 1970 1980 1990 2000

ertapenem

tigecyclin daptomicin linezolid

telithromicin quinup./dalfop. cefepime ciprofloxacin aztreonam norfloxacin imipenem cefotaxime clavulanic ac. cefuroxime gentamicin cefalotina nalidíxico ac. ampicillin methicilin vancomicin rifampin chlortetracyclin streptomycin pencillin G prontosil

The development

of anti-infectives …

Development of anti-infectives

Enhancement of spectrum activity

Avoidance of resistance mechanisms

Improvement of pharmacology (PK/PD)

Development of anti-infectives

Factors fuelling the development of anti-infectives …

1920 1930 1940 1950 1960 1970 1980 1990 2000

tigecyclindaptomicin

linezolidtelithromicin

quinup./dalfop.cefepime

ciprofloxacinaztreonam

norfloxacinimipenem

cefotaximeclavulanic ac.

cefuroximegentamicin

cefalotinanalidíxico ac.

ampicillinmethicilin

vancomicinrifampin

chlortetracyclinstreptomycin

pencillin Gprontosil

1920 1930 1940 1950 1960 1970 1980 1990 2000

tigecyclindaptomicin

linezolidtelithromicin

quinup./dalfop.cefepime

ciprofloxacinaztreonam

norfloxacinimipenem

cefotaximeclavulanic ac.

cefuroximegentamicin

cefalotinanalidíxico ac.

ampicillinmethicilin

vancomicinrifampin

chlortetracyclinstreptomycin

pencillin Gprontosil

ertapenem

1920 1930 1940 1950 1960 1970 1980 1990

new antimicrobial agent

new resistance mechanisms






Antibiotic resistance & development of anti-infectives

The action and reaction principle …

Transference of vanA gene from E. faecalis to S. aureus

Antibiotic resistance: the action and reaction response

Anti-infective agent

Discovery(introduction)

Resistance1st reported

Mechanisms of resistance

Organisms

Penicillin G 1940 (1943) 1940 Penicillinase S. aureus

Streptomycin 1944 (1947) 1947 S12 ribosomal mutations M. tuberculosis

Tetracycline 1948 (1952) 1952 Eflfux Shigella dysenterie

Erythromycin 1952 (1955) 1956 23S rRNA methylation S. aureus

Vancomycin 1956 (1972) 1988, 2004 D-Ala-D-Ala replacement E. faecalis, S. aureus

Methicillin 1959( 1961) 1961 MecA (PPP2a) S. aureus

Gentamicin 1963 (1967) 1969 Modifying enzymes S. aureus

Nalidixic ac. 1962 (1964) 1966 Topoisomerase mutations E. coli

Cefotaxime 1975 (1981) 1981, 1983 AmpC ß-lactamases, ESBL Enterobacteriaceae

Imipenem 1976 (1987) 1986 Adquired carbapenemases P. aeruginosa, S. marcescens

Linezolid 1979 (2000) 1999 23S RNA mutations S. aureus, E. faecalis

Daptomycin 1980 (2004) 2005 ? S. aureus, E. faecalis

Drugs developed to counteract resistance mechanismsYear Relevant resistance at appearance time Antimicrobials developed

1940 Penicillinase-(+) S. aureus Stable penicillins: methicillin, oxacillin, cloxacillin, …1st gen. cephalosporins: cephalotin, cephalexin, …

Tetracycline resistance Doxycycline, minocycline,… tigecycline

Gentamicin resistance Tobramycin, amikacin, isepamicin

1960 Nalidixic acid Norfloxacin, ciprofloxacin, levofloxacin, moxifloxacin

Methicillin resistant S. aureus Quinup.-dalfopristin, linezolid, daptomycin, tigecycline

TEM-1 ß-lactamase producing E. coli ß-lactamase inhibitors: clavulanic, sulbactam, tazobactam 2nd / 3rd gen. cephalosporins: cefotaxime, ceftazidime, …

1980 AmpC hiperproducing gram-(-) rods 4th gen. cephalosporins: cefepimeCarbapenems: imipenem, meropenem, ertapenem, doripenem, panipenem, ...

ESBL producing Enterobacteriaceae Carbapenems: imipenem, meropenem, ertapenem doripenem, panipenem, ...

1990 Penicillin/macrolide R S. pneumoniae Telithromycin

Vancomycin resistant enterococci Quinup.-dalfopristin, linezolid, daptomycin, oritavancin, telavancin


Bacteria Antibiotics

Antibiotic resistance How did antibiotic resistance occur?

Genetic events

- mutations and resistance gene acquisition

Selection (antibiotic density)

- eradication of susceptible populations and dominance of

natural resistant (sub)populations

- co-selection processes (multiresistance)

Dispersion - spread of resistant isolates (clones) or even resistant genes

Lipsitch & Samore. Emerg Infect Dis 2002; 8:347-354Baquero, Coque, Cantón. ASM News 2003; 69; 547-52

Matlay et al. Emerg Infect Dis 2006; 12:183-190

Resistant bacteria

Mutations

XX

Antibiotic resistance: genetic events

Susceptible bacteria

Resistant bacteria

Gene transfer

Antibiotic resistance: mutational events

A natural resistant population (resistant mutants) is always

present (frequency of mutation) in all bacterial populations

The number of resistant mutants increases with the

inoculum

Under antibiotic pressure the susceptible subpopulation isinhibited and the resistant mutants can survive and become dominant within the population (selection)

bacterias resistentes

bacterias sensibles

resistant bacteria

susceptible bacteria

Antibiotic resistance: acquisition

The acquisition of resistance genes in bacteria depends on:

- capacity for sharing ecological niches with other bacteria

- association of the resistant genes with gene capture units (plasmids, transposons, integrons, …)

- integration capacity of resistant genes (recombination)

Under antibiotic pressure susceptible bacteria are eliminated

but not those carrying resistant genes (selection)

Dispersion of resistant bacteria

epidemic & endemic

A

A

mutation

selection

A = antibiotic pressure

fixation of resistant genes and resistant bacteria in bacterial populations

spread

well-adapted clones

allodemic

lateral transfer

Levy SB. Antibiotic resistance: an ecological imbalanceCiba Found Symp. 1997;207:1-9


The use of antibiotics fuels antibiotic resistance

- emergence (mutation and recombination)

- dispersion

- maintenance (fitness)

selection density

amount ofantibiotic

per individual per geographic area

antibiotic use (consumption)

Antibiotic use (consumption)

Do we use a lot of antibiotics? How do we use

antibiotics?

Is there any influence of antibiotic use

on antimicrobial resistance trends?

There is a direct correlation between specific antimicrobial use and antimicrobial resistance (resistant organisms)

- the increase in antimicrobial use increases antibiotic R (but not - the decrease in antimicrobial use decreases antibiotic R

always!)

Higher resistance levels in bacteria belonging to scenarios with high antibiotic density (nosocomial organisms)

Patients with infections due to (multi)resistant organisms have been treated with more antimicrobials

Those areas with higher antibiotic consumption present higher antimicrobial resistance

Prolonged antimicrobial use increases the risk for an infection due to a (multi)resistance organisms

Antimicrobial resistance and consumption: the evidence

Patient level

Antibiotic exposure:

prescriptions, patient charts, local/national databases (e.g. pharmacy information

system, insurance system)Resistance: patient charts, microbiology laboratory information system

Collective level (aggregated data)

Antibiotic consumption: wholesalers, pharmacy purchases, dispensations to wards

Resistance: microbiology laboratory information system

Antimicrobial resistance and consumption: the data

Organisms

- Infecting organisms (sentinel organisms)

- Colonizing organisms

- Epidemic clones

Resistance phenotypes

Resistance genes

Antibiotics

- packages sold

- defined daily dose per 1000 population per day

(DDD/1000/day)

- defined daily dose per 100 bed-days (DDD/100 bed-days)

Antimicrobial resistance and consumption: the data

Antimicrobial resistance and consumption: the evidence


Antibiotic use, ATC group (year of data)

No. of countries

Spearman correlation

(95% CI)p

S pneumoniae 1999/2000

ErythromycinMacrolides, J01FA (1998)

16 0·83 (0·67–0·94) 0·0008

S pneumoniae 2001

Penicillin Penicillins, J01C (2000)

19 0·84 (0·62–0·94) <0·0001

Cephalosporins, J01DA (2000)

0·68 (0·33–0·87) 0·0014

S pyogenes 1999/2000

ErythromycinMacrolides, J01FA and lincosamides, J01FF (1998)

21 0·65 (0·25–0·86) 0·0015

E coli 1999/2000

CiprofloxacinQuinolones, J01M (1999)

14 0·74 (0·35–0·91) 0·0023

Co-trimoxazoleCo-trimoxazole, J01EE01 (1999)

0·71 (0·29–0·90)0·0048

Goossens et al. Lancet 2005; 365: 579-87

Antimicrobial use in the community (Europe)

Cars et al. Lancet 2001; 357:1851-1853

EARS and IMS databases

Antimicrobial use in the community (Europe)(excluding over-the-counter sales)


Antimicrobial use in the community (Europe)(Seasonal variation)


Streptococcus pneumoniae

Farrell, Cantón, Hryniewicz. 16th ECCMID, 2006Farrell, Felmingham. J Antimicrob Chemother 2005; 56: 795-7

Reinert. J Chemother 2004;16 (Suppl 6):35-48

0

5

10

15

20

25

30

35

40

99-00 00-01 01-02 02-03 03-04

Years

% o

f re

sist

ant

isol

ates

Penicillin Erythromycin Levofloxacin Telithromycin

0

5

10

15

20

25

30

35

40

99-00 00-01 01-02 02-03 03-04

Years

% o

f re

sist

ant

isol

ates

Penicillin Erythromycin Levofloxacin Telithromycin

Global resistance trends (42 countries, 5 continents)

PROTEKT Database (1999-2004)

S. pneumoniae - penicillin resistance ( I+R )

Poland 8.3/9.3

1.9

Portugal 3.5/12.9

4.7

Hungary 11.3/26.8

1.4

Germany 4.7/1.3

0.3

Rep. of Ireland2.6/19.7

3.4

The Netherlands 3.4/0.0

0.0

Belgium 5.1/5.1

2.2

Spain 13.4/34.9

17.2

Italy9.8/5.6

0.8

Switzerland 14.4/8.7

2.0

Greece 8.3/1.7

7.0

Austria 2.5/0.6

0.0

Slovak Rep. 20.4/28.6

0.0

Czech Rep.

1.2/4.40.6

France 16.7/47.7

10.2

UK 4.8/1.0

1.0

LowIntermediateHigh

Intermediate / high penicillin resistanceamoxicillin resistance



Penicillin I+R S. pneumoniae and antibiotic consumption

Bronzwaer et al. Emerg Infect Dis 2002; 8:278-282

Pen

I+

R S

. p

neu

mo

nia

e

EARS and IMS databases


Penicillin I+R S. pneumoniae and antibiotic consumption


Poland 14.5

Portugal 12.9

Hungary 35.2

Germany 15.4

Rep. of Ireland17.9

The Netherlands 11.9

Belgium 32.1

Spain 33.8 Italy

35.6Switzerland

17.3Greece

48.6

Austria 11.0

Slovak Rep. 34.7

Czech Rep.

3.8

France 60.6

UK 20.2

S. pneumoniae – erythromycin resistance

LowIntermediateHigh


Erythromycin resistance in S. pneumoniae in Spain

total comsumption

twice a day*

once a day

three times per day

Macrolide comsumption

Granizo et al. J Antimicrob Chemother 2000; 46:767-73

*r=0,886 p<0.01

Antibiotic consumption and resistance

http://jac.oxfordjournals.org/content/vol46/issue5/images/large/MW5281Fig1.jpeg

Escherichia coli from UTI in Europe (14 couuntries)

Kahlmeter et al. J Antimicrob Chemother 2003; 52:1005-10


Escherichia coli from UTI in Europe (14 couuntries)


Kahlmeter et al. J Antimicrob Chemother 2003; 52:1005-10

Antimicrobial use in the hospitals

Higher selection density than in the community

Fewer antimicrobials in the formulary than in the

community

Lower diversification

Cycling strategies

Circulation of multi-drug resistant clones

Maintenance of resistance genes

http://www.abdn.ac.uk/arpac/

Antimicrobial use in the hospitals (Europe)







Hospital Ramón y Cajal (Madrid, Spain)

Antibiotic use and resistance in hospitals as a risk factor

Outbreak (11 patients, 97-98) TEM-4 K. pneumoniae clone

- case control study at Ramón y Cajal University Hospital

Exposure to Odds ratio

Aminoglycosides 10.2

3rd gen. ceph. 17.8

3rd gen. ceph

+ Gen or Tob

21.6

Asensio et al. Clin Infect Dis 2000; 30:55-60

Antibiotic use and resistance in the hospital

Meyer et al, Ann Intern Med, 1993; Rahal et al, J Am Med Assoc, 1998Urban et al. MDR, 2000; Rahaal et al. Clin Infect Dis 2002

Squeezing the resistance balloon

Antibiotic use and resistance in the hospital

MRSA: temporal seriesAberdeen, 1996-2000

A) penicillins + β-lac inhibitors B) macrolides, C) 3rd gen. cephalosporins D) fluoroquinolonesE) tetracyclinesF) aminoglycosides

Monnet et al. Emerg Infect Dis 2004; 10:1432-41

Antibiotic use and resistance in the hospital MRSA: temporal series (Aberdeen, 1996-2000)

Monnet et al. Emerg Infect Dis 2004; 10:1432-41

Antibiotic use and resistance in the hospital P. aeuginosa and fluoroquinolones (USA, 199-2001)

Polk et al. Clin Infect Dis 2004; 39:497-503

The expected results

If an antibiotic use causes antibiotic resistance …

… the decrease in antibiotic use should produce a decrease

in the resistance levels!

- macrolide resistance and S. pyogenes

Antimicrobial resistance and consumption

Seppälä et al. N Eng J Med 199; 337:441-6

0

0,5

1

1,5

2

2,5

3

76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96

Year

0

2

4

6

8

10

12

14

16

18

20

Erythromycin-R

Global comsumption(macrolides)

Macrolides and Streptococcus pyogenes (Finland)

DDD/1000 inhabitants/year % of resistant isolates

Seppälä et al. N Eng J Med 199; 337:441-6

Bergman et al. Clin Infect Dis 2004; 38:1251-6


Lee et al. et al. Infect Control Hosp Epidemiol 2004; 25:832-7

Decrease of 3rd-g ceph. use and decrease of ESBL- K. pneumoniae

The unexpected results

The increase in antibiotic use does not always produce an increment in antibiotic resistance

- fluoroquinolone resistance and S. pneumoniae García-Rey et al. Clin Microbiol Infect 2006; 12 (Suppl 3):55-

66

The decrease in antibiotic use may not produce a decrease in the resistance levels

- ESBLs and 3rd gen. cephalosporins Cobo, Cantón, Soler ICAAC,

2003

- sulphonamide resistance and E. coli Enne et al. Lancet 2001; 28:

357:1325-8


Poland 0.0

Portugal 1.2

Hungría 0.0

GermanyRep. of Ireland

1.7

The Netherlands

0.0

Belgium 0.7

Spain 2.1 Italy

1.5Switzerland

0,9Greece

0.0

Austria 0.0

Slovak Rep. 0.0

Czech Rep. 0.0

France 1.4

UK 1.0


LowIntermediateHigh

S. pneumoniae – levofloxacin resistance


S. pneumoniae and fluorquinolones in Spain

Ciprofloxacin resistance in S. pneumoniae

R >= 2 µg/mlI + R >= 4 µg/ml

Total fluorquinolones consumption in Spain

Garcia-Rey et al. Clin Microbiol Infect 2006; (Suppl 3): 55-66

Inverse correlation between quinolone consumption and resistance to ciprofloxacin in S. pneumoniae by province in Spain

Garcia-Rey et al. Clin Microbiol Infect 2006; (Suppl 3): 55-66

Reduction of antimicrobial use does not always reduce resistance!

• Effect of a national restriction of

sulphonamide prescriptions in the UK

on the prevalence of sulphonamide

resistance in Escherichia coli

- prescribing data

- sulphonamide resistance genes

Prescriptions per year in the UK

(projected from prescribing data

from 500 general practitioners)

Enne, Livermore, Stephens, Hall. Lancet 2001; 28: 357:1325-8

Escherichia coli and sulphonamide resistance in UK

Reduction of antimicrobial use does not always reduce resistance!

Enne, Livermore, Stephens, Hall. Lancet 2001; 28: 357:1325-8

0

10

20

30

40

50

1991 1999

%

Sulphonamide-R Sul-II Sul-I

Genetic linkage of resistance determinants may affect the reduction of resistance within time

ESBL producing Enterobacteriaceae Ramón y Cajal University Hospital (1988-2005)

0255075

100125150175200225250275300325350375400425450

No

of is

olat

es

88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05

Year

M. morganii

K. oxytoca

Citrobacter spp.

Serratia spp.

Enterobacter spp.

Salmonella spp.

K. pneumoniae

E. coli

0

20

40

60

80

100

120

140D

DD

/100

-hos

p-st

ays

PENICILINS CEPHALOSPORINSFLUORQUINOLONES CARBAPENEMSAMINOGLYCOSIDES GLYCOPEPTIDESMACROLIDES CLINDAMICINOTHERS

1996 1997 1998 1999 2000 2001 2002

Cobo, Soler, Cantón, et al. ICAAC, 2003

Antibiotic use at Ramón y Cajal Hospital (Madrid)

0

5

10

15

20

25

1996 1997 1998 1999 2000 2001 2002

% r

esis

ten

ce

0

5

10

15

20

25

DD

D/1

00 p

atie

nt-

stay

s

cefotaxime resistance

ciprofloxacin resistance

global cephalosporin use

global ciprofloxacin use

E. coli resistance and antibiotic use (Hosp. Ramón y Cajal)

Cobo, Soler, Cantón, et al. ICAAC, 2003

Antimicrobial consumption and impact on resistance

The use of antimicrobial agents fuels antimicrobial resistance

A higher antimicrobial resistance is expected to occur in those scenarios with higher selection density (hospitals)

The increment of antimicrobial consumption leads to the

increase of antimicrobial resistance

Conversely, the decrease of antimicrobial use leads to the decrease of antimicrobial resistance

Unexpected results might be observed when correlates antimicrobial consumption and antimicrobial resistance

Documents

Antimicrobial consumption and impact on resistance