Antibiotic treatment in the ICU 1 ICU Fellowship Training Radboudumc
Main issues Delayed identification of microorganisms Impact of critical illness on Pk/Pd High prevalence of antibiotic resistant strains
Delicate balance Antibiotic resistance ICU 30-60% of antibiotics Unnecessary Inappropriate Suboptimal Antibiotic development
Antibacterial resistance across the globe Range of resistance (%) for the main resistant bacteria worldwide (clinical isolates) African region Americas region Eastern Mediterranean region European region Southeast Asia region Western Pacific region Escherichia coli resistant to third generation cephalosporins Escherichia coli: resistance to fluoroquinolones Klebsiella pneumoniae: resistance to carbapenems 2 70 0 48 22 63 3 82 16 68 0 77 14 71 8 58 21 62 8 48 32 64 3 96 0 4 0 11 0 54 0 68 0 55 0 8 MRSA 12 80 21 90 10 53 0.3 60 2 81 4 84 Antimicrobial resistance: global report on surveillance. World Health Organization 2014 De Waele JJ. Intensive Care Med 2018;44:189-196
Antibiotica resistants among migrants Country Migrants with AMR, n Migrants, n Prevalence, % (95% CI) Weight, % Angeletti et al (2016) 39 Dudareva et al (2011) 43 Georgakopoulou et al (2016) 45 Gustaffson et al (2006) 46 Hagleitner et al (2012) 47 Heudorf et al (2016) 48 Krüger et al (2016) 50 Lederer et al (2015) 51 Marschall et al (2006) 53 Oliva et al (2013) 54 Ravensbergen et al (2015) 56 Reinheimer et al (2016) 57 Steger et al (2016) 58 Tenenbaum et al (2016) 60 Valverde et al (2015) 61 Overall (I 2 =98%, p<0 0001) Italy Germany Greece Sweden Netherlands Germany Germany Austria Switzerland Italy Netherlands Germany Germany Germany Spain 12 5 7 13 17 42 18 9 0 0 40 92 12 110 3 48 232 13 23 131 119 73 15 152 96 130 143 105 325 11 25% (13 6 39 6) 2 2% (0 70 5 0) 53 9% (25 1 80 8) 56 5% (34 5 76 8) 13 0% (7 7 20 0) 35 3% (26 8 44 6) 24 7% (15 3 36 1) 60 0% (32 3-83.7) 0 0% (0 0 2 4) 0 0% (0 0 3 8) 30 8% (23 0 39 5) 64 3% (55 9 72 2) 11 4% (6 1 19 1) 33 9% (28 7 39 3) 27 3% (6 0 61 0) 25 4% (19 1 31 8) 6 45% 8 41% 3 34% 4 56% 7 93% 7 34% 7 03% 3 70% 8 46% 8 44% 7 49% 7 51% 7 86% 8 03% 3 46% 100 00% 0% 50% 100% Nellums LB. Lancet Infect Dis 2018;18:796-811
High antibiotic use in the ICU Fig. 1 Elements contributing to high antibiotic consumption in the De Waele JJ. Intensive Care Med 2018;44:189-196
ESBL carrier-ship induces meropenem use OUTCOMERA database 318 ESBL carriers Meropenem initiation No documented infection 63% 9% IVAC Non VAP infection 21% 15% Infection related ventilator-associated complication N = 576 Non ESBL VAP 13% 42% ESBL VAP 3% 56% Barbier F. Intensive Care Med 2018;44:616-626
De Waele JJ. Intensive Care Med 2018;44:189-196
Antibiotic stewardship Rapid identification of patients with bacterial sepsis Better empirical treatment selection Optimized antibiotic dosing with PK-PD models De-escalation when culture result are available Shortening therapy duration
Antibiotic stewardship Rapid identification of patients with bacterial sepsis Better empirical treatment selection Optimized antibiotic dosing with PK-PD models De-escalation when culture result are available Shortening therapy duration
Rapid adequate initiation of antibiotics essential Septic shock (N = 2154) Cumulative effective antimicrobial initiation Survival fraction 1.0 Fraction of total patients 0.8 0.6 0.4 0.2 0.0 0-0.5 0.5-1 1-2 2-3 3-4 4-5 5-6 6-9 9-12 12-24 24-36 > 36 Time from onset hypotension (hrs) Kumar A. Crit Care Med 2006;34:1589-1596
Severe sepsis/septic shock (N = 28150) 0.38 Predicted hospital mortality 0.36 0.34 0.32 0.30 0.28 0.26 0.24 0.22 0.20 0-1 1-2 2-3 3-4 4-5 5-6 > 6 Time to first antibiotics (hrs) Ferrer C. Crit Care Med 2014;42:1749-1755
However with lower disease severity.. Effect of early antibiotic administration less evident Delay in antibiotic treatment in hemodynamically stable patients with suspected infections until infection is confirmed is probably warranted Hranjec T. Lancet Infect Dis 2012;12:774-780
Delay in antibiotics even if given < 6 hours 3 N = 35.000 (Emergency department) Increase absolute mortality / hour delay (%) 2 1 0,3 0,4 1,8 0 Sepsis Severe sepsis Septic shock Liu VX. Am J Respir Crit Care Med 2017;196:856-863
Progression from severe sepsis to septic shock Each hour delay in antibiotics associated with 8% increased conversion to septic shock Whiles BB. Crit Care Med 2017;45:623-629
Can biomarkers predict the presence of sepsis? CRP, strem-1, PCT PCT good marker for community acquired- but not for hospital-acquired infections PCT can rise in various non-infectious diseases or remain low in proven infections (contained infection with local production or delayed rise)
Wacker C. Lancet Infect Dis 2013;13:426-435 Role of biomarkers in diagnosing sepsis?
Cut-off value 1-2 ng/ml Wacker C. Lancet Infect Dis 2013;13:426-435
cterial 27 (17.9) al 35 (23.2) -infection 10 (6.6) PCT in acute exacerbations of COPD 0.28 (0.10 0.90) T < 0. 1 μg/l, n (%) PCT < 0.25 μg/l, n (%) T 0.25 μg/l, n (%) ta unknown, n (%) ocyte count ( 109/L) dian (Q1 Q3) 27 (17.9) 434 3 (2.0) H0 (μg/l) an (SD) 26 (17.2) 0.19 (0.08 0.79) 37 (25.0) 39 (25.8) 33 (22.3) 40 (28.2) 78 (52.7) 63 (44.4) 3 (2.0) 9 (6.3) 15,003 (12,578) 14,825 (10,630) 12,040 (8865 16,775) 12,820 (9607 17,152) N = 302 Fig. 3 Patients receiving antibiotics during the PCT algorithm phase Fig. 4 Effect of the PCT protocol on in-icu (a) and in-hospital (b) antibiotic treatment durations in the groups randomized according to the presence or absence of pneumonia g. 2 Effect of the PCT protocol on all-cause mortality PCT based initiation + duration of therapy vs usual care Discussion control group, p = 0.75, respectively) (Fig. 4). Notathe in-icu antibiotic exposure duration was not nificantly lower in AECOPDs without pneumonia in In this multicenter, randomized, controlled clinical study, the use of PCT-guided antibiotic therapydaubin failed to demc. Intensive Care Med 2018;44:428-437
New diagnostic techniques Real-time multiplex PCR? Matrix-assisted laser desorption/ionization time-offlight mass spectrometry? Identification infecting organism in 1-2 hrs Shorter time to effective therapy, reduced LOS, reduced costs
Are cultures still necessary? 616 blood cultures, 180 pneumonia, 110 sterile fluid/tissue samples PCR-Electrospray Ionization Mass Spectrometry - resultaten beschikbaar < 6 uur Blood cultures PCR/ EIMS + - Total Sens 81% + 55 173 228 Spec 69% - 13 384 397 PPV 24% Total 68 557 625 NPV 97% Sputum culture PCR/ EIMS + - Total Sens 84% + 68 49 117 Spec 53% - 13 55 68 PPV 58% Total 81 104 185 NPV 81% Vincent JL. Crit Care Med 2015;43:2283-2291
Antibiotic stewardship Rapid identification of patients with bacterial sepsis Better empirical treatment selection Optimized antibiotic dosing with PK-PD models De-escalation when culture result are available Shortening therapy duration
Initial antibiotic therapy Empirical broad-spectrum antibiotics based on available local antimicrobial susceptibility patterns, anticipated side effects and previously received antibiotics in the preceding 2 weeks Potential role of surveillance culture Often broad-spectrum β-lactam + amino glycoside
ARREST trial - adding rifampicine for S. Aureus bacteriamia 20 Placebo Rifampicin P = 0.81 P = 0.81 P = 0.01 P = 0.30 % 15 10 18 17 N = 758 13 15 5 0 4 1 1 1 Total events (composite) Failure Recurrence Death without either 14 D of rifampicine/placebo added to standard therapy Thwaites GE. Lancet 2018;391:668-678
Effects of cycling or mixing of antibiotics on antibiotic resistance 100 75 Mixing Hospital A B C D E F G H Sample 10 20 30 40 Cycling N = 1598 9 months periods Prevalence (%) 50 25 0 0 10 20 30 40 0 10 20 30 40 Week number Week number No difference in all cause mortality No effect on antibiotic resistance van Duijn PJ. Lancet Infect Dis 2018;18:401-409