Antimicrobial consumption and impact on resistance

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

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

ertapenem tigecyclin daptomicin linezolid telithromicin quinup./dalfop. cefepime of anti-infectives ciprofloxacin aztreonam norfloxacin imipenem cefotaxime clavulanic ac. cefuroxime gentamicin cefalotina nalidíxico ac. ampicillin methicilin vancomicin rifampin chlortetracyclin streptomycin pencillin G prontosil The development Development of anti-infectives 1920 1930 1940 1950 1960 1970 1980 1990 2000

Development of anti-infectives Factors fuelling the development of anti-infectives 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 Enhancement of spectrum activity Avoidance of resistance mechanisms Improvement of pharmacology (PK/PD) 1920 1930 1940 1950 1960 1970 1980 1990 2000

Antibiotic resistance & development of anti-infectives The action and reaction principle new resistance mechanisms new resistance mechanisms new antimicrobial agent new resistance mechanisms new antimicrobial agent new resistance mechanisms new antimicrobial agent 1920 1930 1940 1950 1960 1970 1980 1990

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

Antibiotic resistance: the action and reaction response Anti-infective agent Discovery (introduction) Resistance 1 st 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 mechanisms Year Relevant resistance at appearance time Antimicrobials developed 1940 Penicillinase-(+) S. aureus Stable penicillins: methicillin, oxacillin, cloxacillin, 1 st gen. cephalosporins: cephalotin, cephalexin, Tetracycline resistance Gentamicin resistance Doxycycline, minocycline, tigecycline Tobramycin, amikacin, isepamicin 1960 Nalidixic acid Norfloxacin, ciprofloxacin, levofloxacin, moxifloxacin Methicillin resistant S. aureus TEM-1 ß-lactamase producing E. coli Quinup.-dalfopristin, linezolid, daptomycin, tigecycline ß-lactamase inhibitors: clavulanic, sulbactam, tazobactam 2 nd / 3 rd gen. cephalosporins: cefotaxime, ceftazidime, 1980 AmpC hiperproducing gram-(-) rods 4 th gen. cephalosporins: cefepime Carbapenems: 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

Antibiotic resistance 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; 8:347-354 Baquero, Coque, Cantón. ASM News 2003; 69; 547-52 Matlay et al. Emerg Infect Dis 2006; 12:183-190

Antibiotic resistance: genetic events Susceptible bacteria Resistant bacteria Gene transfer Resistant bacteria

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 susceptible bacterias sensibles bacteria bacterias resistant resistentes bacteria Under antibiotic pressure the susceptible subpopulation is inhibited and the resistant mutants can survive and become dominant within the population (selection)

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 mutation well-adapted clones selection A spread A = antibiotic pressure A lateral transfer epidemic & endemic fixation of resistant genes and resistant bacteria in bacterial populations allodemic

Antibiotic resistance The use of antibiotics fuels antibiotic resistance - emergence (mutation and recombination) - dispersion - maintenance (fitness) selection density amount of antibiotic per individual per geographic area antibiotic use (consumption) Levy SB. Antibiotic resistance: an ecological imbalance Ciba Found Symp. 1997;207:1-9

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?

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

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

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 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 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 Erythromycin Macrolides, J01FA and lincosamides, J01FF (1998) 21 0 65 (0 25 0 86) 0 0015 E coli 1999/2000 Ciprofloxacin Quinolones, J01M (1999) 14 0 74 (0 35 0 91) 0 0023 Co-trimoxazole Co-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) EARS and IMS databases Cars et al. Lancet 2001; 357:1851-1853

Antimicrobial use in the community (Europe) (excluding over-the-counter sales) Goossens et al. Lancet 2005; 365: 579-87

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

Streptococcus pneumoniae Global resistance trends (42 countries, 5 continents) PROTEKT Database (1999-2004) Farrell, Cantón, Hryniewicz. 16 th ECCMID, 2006 Farrell, Felmingham. J Antimicrob Chemother 2005; 56: 795-7 Reinert. J Chemother 2004;16 (Suppl 6):35-48

S. pneumoniae - penicillin resistance ( I+R ) Portugal 3.5/12.9 4.7 Rep. of Ireland 2.6/19.7 3.4 UK 4.8/1.0 1.0 The Netherlands 3.4/0.0 0.0 Belgium 5.1/5.1 2.2 Low Intermediate High Spain 13.4/34.9 17.2 France 16.7/47.7 10.2 Italy 9.8/5.6 0.8 PROTEKT Database (2002-2003) Germany 4.7/1.3 0.3 Switzerland 14.4/8.7 2.0 Greece 8.3/1.7 7.0 Poland 8.3/9.3 1.9 Czech Rep. 1.2/4.4 0.6 Slovak Rep. 20.4/28.6 0.0 Hungary 11.3/26.8 1.4 Austria 2.5/0.6 0.0 Intermediate / high penicillin resistance amoxicillin resistance

Antimicrobial use in the community (Europe) Penicillin I+R S. pneumoniae and antibiotic consumption EARS and IMS databases Pen I+R S. pneumoniae Bronzwaer et al. Emerg Infect Dis 2002; 8:278-282

Antimicrobial use in the community (Europe) Penicillin I+R S. pneumoniae and antibiotic consumption Goossens et al. Lancet 2005; 365: 579-87

S. pneumoniae erythromycin resistance Rep. of Ireland 17.9 Germany 15.4 Poland 14.5 UK 20.2 The Netherlands 11.9 Czech Rep. 3.8 Slovak Rep. 34.7 Belgium 32.1 Hungary 35.2 Portugal 12.9 Low Intermediate High Spain France 33.8 60.6 Italy 35.6 PROTEKT Database (2002-2003) Switzerland 17.3 Greece 48.6 Austria 11.0

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 *r=0,886 p<0.01 Granizo et al. J Antimicrob Chemother 2000; 46:767-73

Antibiotic consumption and resistance 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

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

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; 30:55-60

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

Antibiotic use and resistance in the hospital MRSA: temporal series Aberdeen, 1996-2000 A) penicillins + β-lac inhibitors B) macrolides, C) 3rd gen. cephalosporins D) fluoroquinolones E) tetracyclines F) 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

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; 337:441-6

Macrolides and Streptococcus pyogenes (Finland) DDD/1000 inhabitants/year 3 2,5 2 1,5 1 0,5 % of resistant isolates 20 18 16 14 12 10 8 6 4 2 Erythromycin-R Global comsumption (macrolides) 0 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 Year 0 Seppälä et al. N Eng J Med 199; 337:441-6 Bergman et al. Clin Infect Dis 2004; 38:1251-6

Antimicrobial resistance and consumption Decrease of 3 rd- g ceph. use and decrease of ESBL- K. pneumoniae Lee et al. et al. Infect Control Hosp Epidemiol 2004; 25:832-7

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 3 rd gen. cephalosporins Cobo, Cantón, Soler ICAAC, 2003 - sulphonamide resistance and E. coli Enne et al. Lancet 2001; 28: 357:1325-8

S. pneumoniae levofloxacin resistance Rep. of Ireland 1.7 Germany Poland 0.0 UK 1.0 The Netherlands 0.0 Czech Rep. 0.0 Slovak Rep. 0.0 Belgium 0.7 Hungría 0.0 Portugal 1.2 Spain France 2.1 1.4 Italy Low 1.5 Intermediate High Switzerland 0,9 Greece 0.0 Austria 0.0 PROTEKT Database (2002-2003)

Antimicrobial resistance and consumption S. pneumoniae and fluorquinolones in Spain R >= 2 µg/ml I + R >= 4 µg/ml Ciprofloxacin resistance in S. pneumoniae 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! 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: 357:1325-8

Reduction of antimicrobial use does not always reduce resistance! 50 40 % 30 20 10 0 1991 1999 Sulphonamide-R Sul-II Sul-I Genetic linkage of resistance determinants may affect the reduction of resistance within time Enne, Livermore, Stephens, Hall. Lancet 2001; 28: 357:1325-8

ESBL producing Enterobacteriaceae Ramón y Cajal University Hospital (1988-2005) No of isolates 450 425 400 375 350 325 300 275 250 225 200 175 150 125 100 75 50 25 0 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 M. morganii K. oxytoca Citrobacter spp. Serratia spp. Enterobacter spp. Salmonella spp. K. pneumoniae E. coli Year

Antibiotic use at Ramón y Cajal Hospital (Madrid) 140 120 PENICILINS FLUORQUINOLONES AMINOGLYCOSIDES MACROLIDES OTHERS CEPHALOSPORINS CARBAPENEMS GLYCOPEPTIDES CLINDAMICIN D D D /1 0 0 -h o s p -s ta y s 100 80 60 40 20 0 1996 1997 1998 1999 2000 2001 2002 Cobo, Soler, Cantón, et al. ICAAC, 2003

E. coli resistance and antibiotic use (Hosp. Ramón y Cajal) 25 25 20 20 % resistence 15 10 5 15 10 5 DDD/100 patient-stays cefotaxime resistance ciprofloxacin resistance global cephalosporin use global ciprofloxacin use 0 1996 1997 1998 1999 2000 2001 2002 0 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