Community Acquired Pneumonia Maximizing the efficacy of antibiotic therapy João Gonçalves Pereira, MD, PhD ICU Director Hospital Vila Franca Xira
Antibiotics and Pneumonia Survival in Bacteremic Pneumococcal Bacteremia Treated with Penicillin or Serum Austrian Ann Intern Med 1964;60:759
Antibiotics and Pneumonia Time until start of antibiotic therapy (CAP) Community acquired Sepsis Houck Arch Intern Med 2004; 164: 637 N = 897 63% CAP Povoa CCM 2009;37:410 Kumar, A Virulence 2014; 5:1
Antibiotics and Pneumonia Pneumonia Bundle Wiemken Semin Respir Crit Care Med 2012;33:213
Early antibiotics and outcome Author n Setting Odds Ratio (death) Author n Setting Odds Ratio (death) Gaieski (Crit Care Med 2010; 38:1045) 261 ED (Shock) First hour OR 0.30 No difference independent of De Groot (Critical Care 2015; 19:194) 1168 3 ED First hour PIRO score OR 0.62 Daniels (Emerg Med J 2010; doi:10.1136) 567 Whole hospital Aggressive antibiotic therapy Surgical ICU: Beforeafter First vs second hour OR 0.59 Hranjec (Lancet Infect Dis 2012;12:774) 201 OR for mortality 2.5 Kumar (Crit Care Med 2006;34:1589) 2154 ED (Shock) Hospital-acquired No difference in mortality up to Puskarich (Crit Care Med 2011;39:12066) 372 Appelboam (Crit Care 2010;14:50) 375 Whole surgical hospital infections First hour 6h after OR diagnostic 0.74 First 3h No improvement OR 0.86 with decrease Levy Villela (Crit Care (Am Med J Emerg 2010; Med 38:1) 2014;32:7) 15022184 Multi-centre ED admitted to the ICU in time to antibiotics (5h to 3h) Barie Pelletier(Surg Infect (Larchmt) Infect (Larch) 2005;6:41) 1999;134:1300) 356 372 Surgical Surgical ICU patients Per hour No difference delay 1.021 0h,>12h, >24h Ferrer Castellanos-Ortega (Crit Care Med (Crit Care Med 2014;42:1749) 17990480 Multi-centre ED: Before-after 2010;38:1036) Progressive Early antibiotics increase in OR risk 0.68, per hour p=0.11 (1.07-1.52) Jalili (Acta Med Iran 2013; 51:454) 145 ED (sepsis) First 2h Inappropriate Davies (Shock 2014;42:185) 7158 Surgical patients OR 0.44 vs. appropriate OR 1.0 No difference in a metanalysis (11 studies included). OR 1.16 Sterling Crit Care Med. 2015;43:1907
Accuracy of sepsis diagnosis Infection rate in patients with presumed sepsis upon presentation Klein Klouwenberg Crit Care 2015;19:319 Over 50% of patients with suspected pneumonia probably did not had infection Antibiotics are of no use if patients are not infected (harm?)
Antibiotics and Pneumonia Pneumonia Bundle Better diagnostic tools Early directed therapy Adequate dose 1 2 Reassess diagnostic PK and antibiotic dose Response to therapy Minimize antibiotic exposure 3 Wiemken Semin Respir Crit Care Med 2012;33:213
Pharmacokinetics Antibiotics Absorption Distribution Elimination PK Effect of the antibiotic at the site of infection Concentration at Infection Site Pathogen MIC/MBC PD Bacterial Killing Toxicity Dose antibiotics to maximize its exposure to bacteria Craig WA - CID 1998; 26.1
Patterns of Antimicrobial Activity Concentration C max Aminoglycosides Metronidazol 4 Area under the concentration curve Azithromycin 2 Fluoroquinolones Glycopeptides Log 10 CFU/ ml 9 8 7 6 5 3 Log 10 CFU/ ml 0 2 4 6 MIC T>MIC Beta-lactams Carbapenems Control ¼ x MIC 1 x MIC 4 x MIC 16 x MIC 64 x MIC 0 2 4 6 8 Time (hours)
Two fold variability of PK parameters (Vd and Cl) Usually increase No clear correlation with clinical parameters Augmented Volume of Distribution Augmented renal Clearance Meropenem ARC Imipenem Piperacillin Cefpirome Cefepime Ceftazidime 10 20 30 40 50 60 Volume of Distribution (L) Udy, Baptista Crit Care Med 2014; 42:520
Dose of Antibiotics Obesity Longo. Pharmacoepidemiology and Drug Safety 2013; 22: 970
Concentration Patterns of Antimicrobial Activity C max :MIC Aminoglycosides MIC and resistance AUC:MIC Vancomycin Fluoroquinolones Concentration C max :MIC Aminoglycosides MIC=0.5 AUC:MIC Vancomycin Fluoroquinolones T>MIC MIC=1 Beta-lactams Carbapenems Time T>MIC Beta-lactams Carbapenems Time Increase in MIC 0.5 1mg/L: Bacteria remain sensitive. However AUC:MIC and Cmax:MIC decrease to one half; T>MIC also decreases Changes in PK may impact clinical efficacy
Bacterial load and mortality Pneumococcal Pneumonia n=353 Rt-PCR positive 26,3% (36,5% positive BC) Septic shock OR 6.29 Mech. Ventilation OR 7.96 Mortality OR 7.08 Patients with positive Rt-PCR Bacterial Load > 10 3 cop/ml (29%) Shock OR 8 Mech. Vent OR 10.5 Mortality OR 5.4 Rello Chest 2009;136:832
Selection of initial antibiotics Single vs. double Use of a macrolide in CAP Sligl Crit Care Med 2014; 42:420
Selection of initial antibiotics Single vs. double The CAPUCI study No Shock Shock Survival HR 1.69 (95%CI 1.09-2.6) Rodriguez Crit Care Med 2007;35:1493 Macrolides p = 0.99 Death HR 0.48 (95%CI 0.23-0.97) Martin-Loeches Intensive Care Med 2010; 36:612
Clinical Success (%) Dose of Antibiotics Clinical Success by PSI Class 100 95 90 85 96.2 n=106 93.4 n=122 92.6 n=27 89.8 n=49 86.3 n=51 750 mg 500 mg 84.4 n=32 80 Class I/II Class III Class IV Patients in Each PSI *Clinically evaluable patients at the 7- to 14-day post therapy visit Dunbar Clin Infect Dis. 2003;37:752
PK/PD guided dose Lower adjusted 90d mortality (p=0.02) Lower LOS (3.9 vs. 5d, p<0.001) Lower Costs ($2485 vs. $3281, p=0.02) Frei, BMC Infect Dis 2011,11: 188
N=432 25 ICUs BLING II study APACHE II 20 90 day survival 74.3% vs. 72.5% HR 0.91 (0.63-1.31) Clinical success Cefepime or ceftazidime AUIC 250 Cure 79% vs. 33%; P = 0.002 T>MIC of 100% Cure 82% vs. 33%; P = 0.002 Mckinnon. Int J Antimicrob Agents 2008; 31: 345 Dulhunty Am J Resp Crit Care Med 2015; 192: 1298
Log 10 cfu/ml Log 10 cfu/ml Optimization of minimum concentration/mic ratio Log 10 cfu/ml Log 10 cfu/ml 12 8 4 0 Placebo 0 1 2 3 4 5 Time (days) 10 8 6 4 2 0 T>MIC=100% & Cmin/MIC=10 0 1 2 3 4 5 Time (days) 10 8 4 0 T>MIC=84% T>MIC=100% Cmin/MIC=1.7+ tobramycin 10 8 6 4 Time (days) 2 0 1 2 3 4 5 0 Time (days) 0 1 2 3 4 5 Tam Antimicrob Agents Chemother 2005; 49. 4920 Wild type Amp C mutant
Vasopressors Cardiac output Diuresis Dose modulation: A new concept of antibiotic therapy in the critically ill patient?,, Joao Goncalves-Pereira MD a,, José-Artur Paiva MD, PhD b a Polyvalent Intensive Care Unit, São Francisco Xavier Hospital, CHLO, Estrada do Forte do Alto do Duque, 1449 005 Lisboa, Portugal Critically ill septic patient b Emergency and Intensive Care Department, Centro Hospitalar São João, Medical School, University of Porto, Porto, Portugal Keywords: Antibiotics; Pharmacokinetics; Dose; Modulation; Intensive care unit Large Volume of Distribution Renal or Hepatic failure Initial High Loading Dose Increased Clearance 2012 Elsevier Inc. All rights reserved. (measure Cr Clearance) Large volume resuscitation Invasive Ventilation Surgical procedure Abstract Considerable evidence has shown that adequate antibiotic therapy is of utmost importance in the critically ill septic patient. However, antibiotic concentration may be insufficient early in infection course. We propose the concept of dose modulation, meaning front-line variability of antibiotic dose, according to patient and microorganism characteristics, followed by its reduction after clinical response and patient recovery. Therefore, dose modulation means concentrating No Yes the largest weight of antibiotics at the front-end, when the microbial load ishigher and the pharmacokinetic changes poses the highest risk of underdosing and nibbling off antibiotic dose, when the sepsis syndrome isimproving, guided by pharmacokinetic and pharmacodynamic data. Adjust Dose accordingly 1. Adequate antibiotic therapy: drug but also dose selection Maintain High Dose The accumulation of evidence that both front-line antibiotic inappropriateness and late appropriateness had significant impact on the outcome of infections in severe sepsis and septic shock patients led to the concept of Reassess after 48-72h Any of: Bacteria with a low MIC Normalization of (measured) Cr Clearance Sepsis resolution Funding: None. Competing interests: None declared. Authors Contributions: JG-P and J-AP both search literature, developed the concept, analyzed, data and wrote the manuscript. Corresponding author. Unidade de Cuidados Intensivos Polivalente, Hospital de São Francisco Xavier, Centro Hospitalar Lisboa Ocidental, Estrada do Forte do Alto do Duque, 1449 005 Lisboa, Portugal. Tel.: +351 21 043 1104/5; fax: +351 21 043 1301. E-mail addresses: joaogpster@gmail.com (J. Goncalves-Pereira), jarturpaiva@gmail.com (J.-A. Paiva). antibiotic de-escalation, meaning that a large-spectrum antibiotic regimen should immediately be started front-line to assure coverage of the pathogen and clinical success. Combination antibiotic therapy has also been proposed in order to enlarge antibacterial spectrum and it may improve patient outcomes, especially in septic shock patients [1]. In parallel, antibiotic streamlining should be done as soon as there is evidence of clinical response and microbiological results are available, to reduce antibiotic pressure and avoid the emergence of antimicrobial resistance [2]. This has been shown to be safe in critically ill patients [3]. Several authors also pointed out that not only should antibiotic therapy be appropriate and early Adjust but also antibiotic Dose dose should be maximized to ensure adequate bactericidal concentration as soon as possible [4,5]. However, the concept ofgonçalves-pereira dose maximization isill-defined Crit Care. and, in our opinion, did not 2013;28:341 translate into the clinical arena.
Accumulation and Toxicity Ceftriaxone 2 g/d Increase 2-3* from D1 to D7 Cr Cl >50 ml/min <50 ml/min Day 1 19,5 μg/ml 46,5 μg/ml Day7 38,5 μg/ml 125 μg/ml Heinemeyer Int Care Med 1990; 16; 448 Betalactamin-induced central nervous side effects include confusion, disturbances of behaviour, hallucinations, asterixis, myoclonic jerks, and generalised convulsive or nonconvulsive seizures. Those are probably underreported but may contribute to morbidity and mortality. Chatellier Int Care Med 2002; 28. 214 May promote mitochondrial damage and shutdown. May interfere with mitochondrial biogenesis and delay recovery. Singer. Plos Med 2005. e167
Duration of Antimicrobial Activity Reduction of exposure 3-7 d vs. 7-10 d No difference in outcomes
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