Antimicrobial consumption and impact on resistance

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Antimicrobial consumption and impact on resistance
5th ESCMID School of Clinical Microbiology and
Infectious Diseases Santander, Spain 10-16
June, 2006

• Dr. Rafael Cantón
• Servicio de Microbiología. Hospital
  Universitario Ramón y Cajal
• Associated Professor. Facultad de Farmacia.
  Universidad Complutense Madrid, Spain

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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
  200410 (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 5450-59

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Development of anti-infectives
The development of
anti-infectives
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Development of anti-infectives
Factors fuelling the development of
anti-infectives

• Enhancement of spectrum activity
• Avoidance of resistance mechanisms
• Improvement of pharmacology (PK/PD)

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Antibiotic resistance development of
anti-infectives
The action and reaction principle
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Transference of vanA gene from E. faecalis to
S. aureus
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Antibiotic resistance the action and reaction
response
Anti-infective agent Discovery (introduction) Resistance 1st 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
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Drugs developed to counteract resistance
mechanisms
Year Relevant resistance at appearance time Antimicrobials developed
1940 Penicillinase-() S. aureus Stable penicillins methicillin, oxacillin, cloxacillin, 1st gen. cephalosporins cephalotin, cephalexin,
1940 Tetracycline resistance Doxycycline, minocycline, tigecycline
1940 Gentamicin resistance Tobramycin, amikacin, isepamicin

1960 Nalidixic acid Norfloxacin, ciprofloxacin, levofloxacin, moxifloxacin
1960 Methicillin resistant S. aureus Quinup.-dalfopristin, linezolid, daptomycin, tigecycline
1960 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 cefepime Carbapenems imipenem, meropenem, ertapenem, doripenem, panipenem, ...
1980 ESBL producing Enterobacteriaceae Carbapenems imipenem, meropenem, ertapenem doripenem, panipenem, ...

1990 Penicillin/macrolide R S. pneumoniae Telithromycin
1990 Vancomycin resistant enterococci Quinup.-dalfopristin, linezolid, daptomycin, oritavancin, telavancin
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Antibiotic resistance
Antibiotics
Bacteria
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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
8347-354 Baquero, Coque, Cantón. ASM News 2003
69 547-52 Matlay et al. Emerg Infect Dis 2006
12183-190
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Antibiotic resistance genetic events
Susceptible bacteria
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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 is
• inhibited and the resistant mutants can survive
  and become
• dominant within the population (selection)

bacterias sensibles
susceptible bacteria
bacterias resistentes
resistant bacteria
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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)

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Dispersion of resistant bacteria
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Antibiotic resistance

• The use of antibiotics fuels antibiotic
  resistance
• - emergence (mutation and recombination)
• - dispersion
• - maintenance (fitness)
• selection density

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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?

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Antimicrobial resistance and consumption the
evidence

• 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

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Antimicrobial resistance and consumption the
data

• 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

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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)

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Antimicrobial resistance and consumption the
evidence
Antibiotic resistance Antibiotic use, ATC group (year of data) No. of countries Spearman correlation (95 CI) p
S pneumoniae 1999/2000 Erythromycin Macrolides, J01FA (1998) 16 083 (067094) 00008
S pneumoniae 2001 Penicillin Penicillins, J01C (2000) 19 084 (062094) lt00001
Cephalosporins, J01DA (2000) 068 (033087) 00014
S pyogenes 1999/2000 Erythromycin Macrolides, J01FA and lincosamides, J01FF (1998) 21 065 (025086) 00015
E coli 1999/2000 Ciprofloxacin Quinolones, J01M (1999) 14 074 (035091) 00023
Co-trimoxazole Co-trimoxazole, J01EE01 (1999) 071 (029090) 00048
Goossens et al. Lancet 2005 365 579-87
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• Antimicrobial use in the community (Europe)

EARS and IMS databases
Cars et al. Lancet 2001 3571851-1853
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• Antimicrobial use in the community (Europe)
• (excluding over-the-counter sales)

Goossens et al. Lancet 2005 365 579-87
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• Antimicrobial use in the community (Europe)
• (Seasonal variation)

Goossens et al. Lancet 2005 365 579-87
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Streptococcus pneumoniae
Global resistance trends (42 countries, 5
continents)
PROTEKT Database (1999-2004)
Farrell, Cantón, Hryniewicz. 16th ECCMID,
2006 Farrell, Felmingham. J Antimicrob Chemother
2005 56 795-7 Reinert. J Chemother 200416
(Suppl 6)35-48
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S. pneumoniae - penicillin resistance ( IR )
Germany 4.7/1.3 0.3
Rep. of Ireland 2.6/19.7 3.4
Poland 8.3/9.3 1.9
Czech Rep. 1.2/4.4 0.6
UK 4.8/1.0 1.0
Slovak Rep. 20.4/28.6 0.0
The Netherlands 3.4/0.0 0.0
Hungary 11.3/26.8 1.4
Belgium 5.1/5.1 2.2
Austria 2.5/0.6 0.0
Portugal 3.5/12.9 4.7
France 16.7/47.7 10.2
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
PROTEKT Database (2002-2003)
Intermediate / high penicillin resistanceamoxicil
lin resistance
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• Antimicrobial use in the community (Europe)
• Penicillin IR S. pneumoniae and antibiotic
  consumption

EARS and IMS databases
Pen IR S. pneumoniae
Bronzwaer et al. Emerg Infect Dis 2002 8278-282
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• Antimicrobial use in the community (Europe)
• Penicillin IR S. pneumoniae and antibiotic
  consumption

Goossens et al. Lancet 2005 365 579-87
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S. pneumoniae erythromycin resistance
Germany 15.4
Rep. of Ireland 17.9
Poland 14.5
UK 20.2
Czech Rep. 3.8
Slovak Rep. 34.7
The Netherlands 11.9
Hungary 35.2
Belgium 32.1
Austria 11.0
Portugal 12.9
Spain 33.8
France 60.6
Italy35.6
Switzerland 17.3
Greece 48.6
PROTEKT Database (2002-2003)
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Antibiotic consumption and resistance
Erythromycin resistance in S. pneumoniae in Spain
Macrolide comsumption
total comsumption
twice a day
three times per day
once a day
r0,886 plt0.01
Granizo et al. J Antimicrob Chemother 2000
46767-73
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Antibiotic consumption and resistance
Escherichia coli from UTI in Europe (14
couuntries)
Kahlmeter et al. J Antimicrob Chemother 2003
521005-10
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Antibiotic consumption and resistance
Escherichia coli from UTI in Europe (14
couuntries)
Kahlmeter et al. J Antimicrob Chemother 2003
521005-10
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• 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

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• Antimicrobial use in the hospitals (Europe)

http//www.abdn.ac.uk/arpac/
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• Antimicrobial use in the hospitals (Europe)

http//www.abdn.ac.uk/arpac/
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• Antimicrobial use in the hospitals (Europe)

http//www.abdn.ac.uk/arpac/
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• Antimicrobial use in the hospitals (Europe)

http//www.abdn.ac.uk/arpac/
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Antibiotic use and resistance in hospitals as a
risk factor
Hospital Ramón y Cajal (Madrid, Spain)

• 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 3055-60
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Antibiotic use and resistance in the hospital
Squeezing the resistance balloon
Meyer et al, Ann Intern Med, 1993 Rahal et al, J
Am Med Assoc, 1998 Urban et al. MDR, 2000 Rahaal
et al. Clin Infect Dis 2002
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Antibiotic use and resistance in the hospital
MRSA temporal series Aberdeen, 1996-2000
A) penicillins ß-lac inhibitors B) macrolides,
C) 3rd gen. cephalosporins D)
fluoroquinolones E) tetracyclines F)
aminoglycosides
Monnet et al. Emerg Infect Dis 2004 101432-41
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Antibiotic use and resistance in the hospital
MRSA temporal series (Aberdeen, 1996-2000)
Monnet et al. Emerg Infect Dis 2004 101432-41
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Antibiotic use and resistance in the hospital
P. aeuginosa and fluoroquinolones (USA,
199-2001)
Polk et al. Clin Infect Dis 2004 39497-503
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Antimicrobial resistance and consumption

• 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

Seppälä et al. N Eng J Med 199 337441-6
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Macrolides and Streptococcus pyogenes (Finland)
DDD/1000 inhabitants/year of
resistant isolates
Seppälä et al. N Eng J Med 199 337441-6
Bergman et al. Clin Infect Dis 2004 381251-6
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Antimicrobial resistance and consumption
Decrease of 3rd-g ceph. use and decrease of
ESBL- K. pneumoniae
Lee et al. et al. Infect Control Hosp Epidemiol
2004 25832-7
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Antimicrobial resistance and consumption

• 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 3571325-8

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S. pneumoniae levofloxacin resistance
Germany
Poland 0.0
Rep. of Ireland 1.7
UK 1.0
Czech Rep. 0.0
Slovak Rep. 0.0
The Netherlands 0.0
Hungría 0.0
Belgium 0.7
Portugal 1.2
Austria 0.0
France 1.4
Spain 2.1
Italy1.5
Switzerland 0,9
Greece 0.0
PROTEKT Database (2002-2003)
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Antimicrobial resistance and consumption
S. pneumoniae and fluorquinolones in Spain
Ciprofloxacin resistance in S. pneumoniae
R gt 2 µg/ml I R gt 4 µg/ml
Total fluorquinolones consumption in Spain
Garcia-Rey et al. Clin Microbiol Infect 2006
(Suppl 3) 55-66
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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
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Reduction of antimicrobial use does not always
reduce resistance!
Escherichia coli and sulphonamide resistance in UK
Prescriptions per year in the UK (projected from
prescribing data from 500 general practitioners)

• 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

Enne, Livermore, Stephens, Hall. Lancet 2001 28
3571325-8
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Reduction of antimicrobial use does not always
reduce resistance!
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ESBL producing Enterobacteriaceae Ramón y Cajal
University Hospital (1988-2005)
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• Antibiotic use at Ramón y Cajal Hospital (Madrid)

1996 1997 1998 1999
2000 2001 2002
Cobo, Soler, Cantón, et al. ICAAC, 2003
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E. coli resistance and antibiotic use (Hosp.
Ramón y Cajal)
Cobo, Soler, Cantón, et al. ICAAC, 2003
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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

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