«Antibiotic Stewardship» programmes & antibiotic resistance

«Antibiotic Stewardship» programmes & antibiotic resistance Winfried V. Kern Abteilung Infektiologie Universitätsklinikum Freiburg www.if-freiburg.de

Agenda Definition Healthcare quality & patient safety aspects Research aspects

What is Antibiotic Stewardship? ongoing effort by a healthcare institution to optimize antimicrobial use among hospitalized patients to... - improve patient outcomes - ensure cost-effective therapy, and - reduce adverse sequelae of antimicrobial use (including antimicrobial resistance). MacDougall & Polk CMR 2005

What is Antibiotic Stewardship? system ongoing effort by a healthcare institution to optimize antimicrobial use among hospitalized patients to... - improve patient outcomes - ensure cost-effective therapy, and - reduce adverse sequelae of antimicrobial use (including antimicrobial resistance). MacDougall & Polk CMR 2005

The development of new antibiotics without having mechanisms to ensure their appropriate use is much like supplying your alcoholic patients with a finer brandy. Dennis Maki 1998

assumptions prescribing is (often) suboptimal

assumptions prescribing is (often) suboptimal (and often too excessive)

assumptions prescribing is (often) suboptimal (and often too excessive) and induces resistance

assumptions prescribing is (often) suboptimal (and often too excessive) and reduces resistance optimized (and/or reduced) prescribing improves outcomes and can minimize or even reverse antimicrobial resistance

Bratzler et al Arch Surg 2005

European data (ESAC-PPS 2006*) *20 hospitals, 11,571 patients, 30% with antibiotics Ansari et al CID 2009

European data (ESAC-PPS 2008*) *50 hospitals, 28 countries ESAC investigators 2011

European data (ESAC-PPS 2010*) surgical prophylaxis exceeded one day in 61% of cases *66 hospitals, 23 countries Zarb et al Eurosurv 2012

Burden of hospital-wide inadequate antibiotic prescriptions 9% n=776 Turkey 2009 11% n=107 France 2003 15% n=104 France 2009 20% n=1079 UK 2007 20% n=2306 Israel 2001 22-27% n=539 Switzerland 2007 24% n=166 Spain 2003 29% n=493 Croatia, 2005 17-37%, n=1270 Switzerland 2010 30% n=129 USA 2003 31% n=177 Italy 2008 35% n=105 France 2003 36% n=281 Turkey 2003 37% n=938 Netherlands 2007 43% n=189 Spain 2003 44% n=378 Turkey 2005 47% n=223 Turkey 2005 47% n=173 Switzerland 2004 54% n=156 Turkey 2000 64% n=438 Croatia 2007 66% n=122 France 2007

assumptions prescribing is (often) suboptimal (and often too excessive) and induces resistance

60 50 Taiwan Spain % Penicillin-nichtempfindliche Pneumokokken 40 30 20 10 0 0 This is where a large graphic or chart can go. 10 Greece 20 USA Portugal Ireland Canada Luxemburg Iceland Austria Italy UK Belgium Australia Germany Sweden Finland Denmark Netherlands Norway 30 France 40 Antibiotikaverbrauch (definierte Tagesdosen [DDD]/1000 Tage) Albrich et al. Emerg Infect Dis 2004

Group-level data Group-level data 60 50 Imipenem DDD per 1000 pt days 40 30 100% 95% 90% 85% 80% 75% 70% 20 10 0 1994 1995 1996 1997 1998 Clin Infect Dis 2001; 33: 1462-68 Gram-negative bacilli Percent imipenem-susceptible

Individual-level data Probability of resistance 0.30 0.20 0.10 Adjusted hazard ratio: 5.7 (95% CI, 3.7-8.7) No imipenem 0.00 0 20 40 60 80 Days in hospital Imipenem Clin Infect Dis 2001; 33: 1462-68

Limitations to consider the limited evidence provided by purely observational (vs interventional studies) individual-level or group-level analysis (ecological bias)

7 FQR-EC and FQ Use 100 6 E. coli (r = 0.79; p = 0.002) 90 80 % FQ Resistance 5 4 3 2 70 60 50 40 30 DDD/1000 patient-days 20 1 10 0 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 0 Lautenbach, SHEA, 2002

FQR-EC and the Dow Jones Index 7 12000 6 E. coli (r=.96; p<.001) 10000 % FQ Resistance 5 4 3 2 8000 6000 4000 DJIA 1 2000 0 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 0 Courtesy: Y. Carmeli

Interventions Endpoint: prescribing quality local guidelines, audit/education with feedback improvement in antimicrobial prescription included among the annual objectives linked to economic incentives in every department CMI 2013

Cisneros et al CMI 2013

Limitations consider endpoints prescribing density prescribing quality cost (from which perspective) patient outcomes vs microbial endpoints)

Drug resistance in E. coli without apparent selection pressure Bean et al. JAC 2005

Limitations to consider design of interventional studies experimental (e.g. cluster-randomized) vs quasiexperimental (e.g. controlled before/after) analysis (e.g. time-series analysis, adverse events)

10 Intervention to Reduce Use of Alert Antibiotics 8 DDD/100 bed-days 6 4 2 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 Months Change: DDD/100 P t test +0.54 0.2 Slope -0.266 <0.001 Ansari et al JAC 2003 Courtesy: Peter Davey, Dundee (UK)

Baseline Intervention Postintervention Kim et al JAC 2008

Limitations sustainability often not described which component is the most critical? (and needs most investment)

Limitations background epidemiology may be different confounding: cultural environment & prevalent prescribing etiquette risk for limited transferability/generalizability?? be aware of potentially adverse effects!!

assumptions & strategies what is optimized and/or reduced? no use by indication shorter treatment PK/PD-optimized treatment (dosing) use (or switch to) the ecologically ( collateral damage ) best-performing drugs

e.g. Bronchitis

e.g. Uncomplicated UTI https://www.escmid.org/escmid_library/online_lecture_library/material/?mid=25322

double-blind trial n=253 women (18-70 years old) diclofenac vs norfloxacin for 3 days (with fosfomycin 3 g as rescue treatment) resolution of symptoms (day 3): 50% vs 77% (risk difference 27%, 95%CI 15-38%) 61% of patients in the diclofenac group ever consumed antibiotics https://www.escmid.org/escmid_library/online_lecture_library/material/?mid=25322

Macrolide resistance among oral streptococci Malhotra-Kumar et al. Lancet 2007; 369:482-490

Makrolide verändern nachhaltig die Mundhöhlenflora Amoxicillin auch?? Plazebokontrollierte Studie mit Amoxicillin (3x1g, n=37) oder Plazebo (n=38) über 1 Woche Rachenspülungen untersucht bis Tag 28 auf Streptokokken mit verminderter Empfindlichkeit auf Penicillin und Amoxicillin Ergebnisse: Malhotra-Kumar et al; K-1579

Fluoroquinolone studies Some milestone studies, e.g. the 3F (French Fluoroquinolone Free-Study): multicenter trial showing substantial MRSA reduction following a 90% fluoroquinolone reduction (Charbonneau et al CID 2006) (!!)

Ceph + Fluorquinolone studies Recently many more 3C and 3C+ studies 3C: Ceph + Cipro/other FQs = C. difficile 3C+: Ceph + Cipro/other FQs = C. difficile ± ESBL ± MRSA

Talpaert et al JAC 2011

[109] Dancer et al IJAA 2013

Summary Stewardship is important but complex Best evidence so far regarding impact on C.difficile infection Very limited evidence for impact on MDR gram-negatives Many more interventional studies (hospital and outpatient setting) are needed