Guess or get it right? Antimicrobial prescribing in the 21 st century Robert Masterton
Traditional Treatment Paradigm Conservative start with workhorse antibiotics Reserve more potent drugs for non-responders 2
New Treatment Paradigm Hit hard and early with appropriate antibiotic(s) Short treatment duration De-escalate escalate where possible 3
The Effect of the Traditional Approach Inappropriate therapy (%) 50 45 40 34 30 20 17 10 4 0 Community-acquired infection Hospital-acquired infection Hospital-acquired after prior therapy for community-acquired Kollef et al. Chest 1999;115:462 474
Mortality Impact of Inadequate Therapy Garnacho-Montero 5 Luna Álvarez-Lerma Adequate Inadequate Rello Kollef Clec'h Ventilator Associated Pneumonia survivor 0 20 40 60 80 100 Luna C, et al. Chest 1997; 111: 676-685 685 Álvarez-Lerma F, et al. Intensive Care Med 1996; 22: 387-394 394 Rello J, et al AmJ Resp Crit Care Med 1997; 156; 196-200 Kollef MH, et al. Ann Inter Med 1995; 122: 743-748 748 Clec h C, et al. Intensive Xare Med 2004; 30: 1327-1333 1333 Garnacho-Montero J, et al. Intensive Care Med 2005; 31: 649-- --55
Mortality Impact of Inadequate Therapy 6 Kang** Zaragoza Valles* Ibrahim Adequate Inadequate Bacteremia survivor 0 20 40 60 80 * Community-acquired bacteremia ** Resistant Gram-Negative microorganisms Ibrahin EH, et al. Chest 2000; 118: 146-155 Valles J, et al Chest 2003; 123: 1615-1624 Zaragoza R, et al. Clin Microbiol Infect 2003; 9; 412-418 Kang CI, et al. Antimicrob Agents Chemother 2005; 49: 760-766
What is the new treatment paradigm? Start with the appropriate empiric antibiotic first in nosocomial infections If appropriate, change antibiotic dosage or therapy based on resistance and pathogen information Recognise that prior antimicrobial administration is a risk factor for the presence of resistant pathogens Know the unit s s resistance profile and choose antibiotics accordingly Administer antibiotics at the right dose for the appropriate duration 7
Where are we now? What do we know about de-escalation? escalation? What do we know about individual organism/condition settings? What do we know about the best way to use the new treatment paradigm? 8
What De-escalation escalation means. Start with broad spectrum appropriate agent Stop if infection unlikely Change to a narrower spectrum agent Use single rather than multiple agents Shorten the course of therapy as much as possible 9 Vidaur. Resp Care 2005, 50: 965 974.
De-escalation escalation in VAP Change of therapy was documented in 56.2% De-escalation escalation = 31.4% (increasing to 38% if isolates were sensitive) De-escalation mortality rate lower than those who continued initial regimen (18% vs 43%; p<0.05) Inappropriate antibiotic therapy = 9% of cases and associated with 14.4% excess mortality De-escalation escalation lower (p <.05) with nonfermenting Gram-negative bacilli (2.7% vs. 49.3%) and in late- onset pneumonia (12.5% vs. 40.7%) When the pathogen remained unknown, half of the patients died and de-escalation escalation was not performed 10 Rello J, et al. Crit Care Med 2004;32:2183 2190
De-escalation escalation in Practice Mortality % 50 40 30 20 10 De-escalated (n=88) No change (n=245) Escalated (n=61) 11 % Patterns of Modification 100 80 60 40 20 0 Quinolone Ureido/Mono Cefepime Carbapenem Kollef MH. Chest 2006; 129: 1210-1218
Guidelines and De-escalation escalation 12 ICU imipenem-based regimen After D3, therapy based on susceptibility results Better empirical cover (81 vs 46%; p<0.01) No change in imipenem resistance rates Soo Hoo et al. Chest 2005;128:2778 87
How to improve de-escalation? escalation? Tracheal Aspirate (n = 81) De-escal escal (21%) No BAL (n=62) De-escal escal (66%) No 13 15D Mortality 28D Mortality LOS ICU LOS Hospital * = p < 0.05 5.8% 34.3% 4.8% 23.8% 11.6% 45.3% 12.1% 38% 17.2 +/- 1.6 22.4 +/- 6.4 17.2 +/- 1.1 23.2 +/- 6 23.1 +/- 4.4* 29.9 +/- 11.1 23.8 +/- 2.4* 29.8 +/- 11.4 Giantsou et al. Intensive Care Med. 2007:33:1533-40.
De-escalation escalation Dilemmas 14 When to de-escalate escalate to a stop Day 3 and Microbiology negative No Systemic Inflammatory Response Syndrome (SIRS) White blood cell count and temperature not markedly and increasingly abnormal When not to de-escalate escalate and to consider escalation Day 3 and Microbiology negative Patient clinically septic SIRS Markedly abnormal temperature Markedly abnormal white blood cell count
Do you practice de-escalation therapy? 1. Yes 2. No 82% 18% 15 Yes No
In my unit, most of my colleagues practice de-escalation: escalation: 1. True 2. False 58% 42% 16 True False
New data disease specific ESBL Predictors of mortality in patients with BSI caused by ESBL-producing Enterobacteriaceae 70 60 59.5 p<0.001 Mortality (%) 50 40 30 20 10 18.5 0 Inadequate initial therapy (n=89) Adequate initial therapy (n=97) 17 n=186 Tumbarello et al. Antimicrob Agents Chemother 2007;51:1987 1994 1994
New data disease specific ESBL Clinical impact of bacteraemia with ESBL-producing Enterobacteriaceae 70 60 Cases Controls Incidence (%) 50 40 30 20 10 0 Mortality Mortality due to infection Delay in appropriate therapy Discharged to chronic care 18 All differences = p < 0.05 Schwaber et al. Antimicrob Agents Chemother 2006; 50: 1257-1262
New data recognising the risks! Risk factors for inadequate treatment of VAP = Multidrug-resistant resistant bacteria (OR = 3.07), polymicrobial infection (OR = 3.67) and late-onset VAP (OR = 2.93) Adequate treatment n=82 Inadequate treatment n=69 1.0 Cumulative survival 0.8 0.6 0.4 0.2 Adequate Inadequate 19 0 0 7 14 21 28 Time after VAP onset (days) Teixeira et al. J Hosp Infect 2007;65:361 367 367
New data the speed of delay! Survivial (%) 20 90 80 70 60 50 40 30 20 10 0 Each hour of delay carries 7.6% reduction in survival 0.5 1 2 3 4 5 6 Delay in treatment (hours) from hypotension onset Kumar et al. Crit Care Med 2006; 34:1589-1596.
New data the time window 142 patients, 3 intensive care units (ICUs) in France, invasive diagnosis for ventilator- associated pneumonia (VAP) Adequate vs inadequate antibiotic therapy on Day 0 Adequate antibiotic therapy on Day 2 rises to 92% LOD score 4 4 (n=70) Median (range) LOD at first suspicion of VAP Median (range) SAPS II at first suspicion of VAP Adequate antibiotic (n=63) Inadequate antibiotic (n=79) P-value 3 (2 4) 3 (2 4) 0.54 34 (28 37) 35 (29 40) 0.79 ICU death 2/27 (7%) 16/43 (37%) 0.006 Hospital death 4/27 (15%) 19/43 (44%) 0.01 LOD = logistic organ dysfuncftion SAPS II = simplied acute physiologic score 21 Clec`h et al. Intensive Care Med 2004;30:1327 1333 1333
New data do not wait for results! Mortality (%) n=75 70 60 50 40 30 20 10 0 52 Switching after susceptibility results p<0.001 18 Adequate treatment within a a few hours 22 Tumbarello et al. Antimicrob Agents Chemother 2007;51:1987 1994 1994
New data putting things together Effect of 2 day delay in appropriate therapy for 30-day mortality in Pseudomonas spp. bacteraemia 50 44% p=0.03 40 30-day mortality (%) 30 20 10 19% 20% 19% 23 0 <12 12 24 24 25 52 52 >52 Delay in appropriate therapy (hours) Lodise et al. Antimicrob Agents Chemother 2007;51:3510 3515 3515
New data is right a constant? Non-survivors Survivors p<0.001 50 p=0.24 p=0.01 44.4 n=97 40 p=0.40 36.7 34.2 Patients (%) 30 20 10 27.8 14 22.2 5.5 10.1 0 Aminoglycosides (n=20) β-lactam/ β-lactamase inhibitors (n=33) Carbapenems (n=28) Ciprofloxacin (n=16) 24 4 of Cipro failed isolates had a mutation at codon 83 of gyra, and other 4 qnrb gene detected Tumbarello et al. Antimicrob Agents Chemother 2007;51:1987 1994 1994
New data right and resistance 40 62 50 Non-adequate Adequate 30 Frequency (%) 20 10 0 25 111 26 362 24 12 9 0 1 2 3 Number of resistances Frequency of the appropriateness of empiric antimicrobial therapy (a) and proportion of deaths (b) in relation to the number of antibiotics to which the E. coli isolated from blood cultures was non-susceptible Peralta et al. J Antimicrob Chemother 2007;60:855 886 886
New data right and resistance 20 Dead Mortality (%) 15 10 363 118 78 67 10 Surviving Adequacy of empiric antibiotic treatment is an independent risk factor for mortality in E. coli bacteraemia 5 8 0 26 12 5 0 1 2 3 Number of resistances Peralta et al. J Antimicrob Chemother 2007;60:855 886 886
New data cost and the paradigm ESBL production in Enterobacteriaceae bacteremia Outcome Mortality Length of stay Delay in appropriate therapy Cost of hospitalisation OR (95% CI) or ME 3.6 (1.4-9.5) 1.56 25.1 (10.5-60.2) 1.57 P-value 0.008 0.001 <0.001 0.003 CI, confidence interval; ME, multiplicative effect 27 Schwaber et al. Antimicrob Agents Chemother 2006; 50: 1257-1262
New data cost and the paradigm Economic impact of bacteraemia with ESBL-producing Enterobacteriaceae Cost (US$) 50000 40000 30000 20000 10000 Cases Controls Cost of short-term term meropenem treatment: 1 week: 601.65 10 days: 859.50 Mean increase in equivalent cost attributable to ESBL production is $9620 ( 5288) 0 28 Average hospital cost Schwaber et al. Antimicrob Agents Chemother 2006; 50: 1257-1262
ESBL rapid testing to improve outcomes Outcome E-test (167) Control (83) P Test Fever; mean days ± SD 4.61 ± 5.06 7.84 ± 6.24 < 0.01 Antibiotic therapy; mean days ± SD 15.72 ± 9.47 18.92 ± 10.92 0.02 DDD: mean days ± SD 31.43 ± 24.47 42.72 ± 34.13 0.01 Median cost ( ) 666 (236-1360) 984 (437-1601 0.03 % adequate days of antibiotic 95.22 76.26 < 0.01 % adequate days DDD antibiotic 91.28 68.26 < 0.01 CDAD; number & percentage 3 (1.8) 8 (9.6) < 0.01 Median days ventilated post VAP 8 (3-19) 12 (6-21) 0.04 29 250 episodes of VAP Bouza et al. Clin Infect Dis. 2007;44:382-7. 7.
How best to get the best? The Care Bundle Approach Specifically selected care elements From evidence based guidelines Implemented together provide improved outcomes compared to individual elements alone 30
The New Paradigm in a Care Bundle Secondary analysis of prospective before after study Intervention: ED sepsis bundle Bundle components Patient identification Fluid resuscitation Vasopressor administration Antibiotic recommendations 31 Shorr et al. Crit Care Med. 2007;35:1416-7. 7.
The New Paradigm in a Care Bundle Mortality reduced with protocol from 48.3% to 30.0% (p=0.04) 100 000 Total Group 80 000 Survivors Cost per patient (US $) 80 000 60 000 40 000 20 000 p=0.009 Total cost (US $) 60 000 40 000 20 000 0 0 32 Before Group After Before Group After Shorr et al. Crit Care Med. 2007;35:1416-7. 7.
The New Paradigm in a Care Bundle 2,000 Before After 1,600 Costs (US$ x 1000) 1,200 800 400 Total cost differential: $573,000 33 0 Total ICU Ward Pharmacy Lab Rad RT ED OR Misc Shorr et al. Crit Care Med. 2007;35:1416-7. 7.
The New Paradigm in a Care Bundle Reduction in LOS is main driver of costs 1.0 0.8 Pre-intervention Post-intervention Proportion of subjects remaining hospitalised 0.6 0.4 0.2 p=0.0023 Median LOS Pre: 10 days Post: 7.5 days 0.0 0 10 20 30 40 34 Length of stay (days) Shorr et al. Crit Care Med. 2007;35:1416-7. 7.
Conclusions 35 What we know: Getting it right first time in serious sepsis is proven Treatment must be guided by local data The new paradigm is just a part of sepsis management The new paradigm saves lives and money What we do not know Where does the new paradigm not work How can the new paradigm best be implemented What is the full picture of benefits realisation against the new paradigm