Optimizing Antibiotic Therapy in the ICU For Pneumonia Current and Future Approaches Andrew F. Shorr, MD, MPH Washington Hospital Center Georgetown Univ.
Disclosures I have served as a consultant to, researcher/investigator for, or spoken for: Astellas Astra Zeneca Bayer Cubist Forest Pfizer Tetraphase Theravance
61 year-old female with asthma & diabetes 2130: Presents to ED with violent cough, productive of green sputum, fevers to 104 F, & vomiting x 10 Levofloxacin in June 2013 ED Vitals: Tmax 38.6 C, BP 60/38, HR 124, RR 30, SaO2 85% 3 L Oxygen, cefepime + vancomycin, 3 L NS, blood cultures, RIJ central line, dopamine then norepi, CVP, S CV O2 0100: arrives MICU
Clinical Deterioration 0530: Norepi weaned off, 6L NC, moxifloxacin MRSA nasal PCR: negative 1200: SaO2 86%, oxygen, 7.28/45/63 1330: Chest X-Ray 1530: intubate 1700: BAL, vancomycin BAL >104 MRSA Vancomycin trough: 10 to 24 Vancomycin MIC: 2 mcg/ml
The Dilemma Appropriate antibiotics key determinant of outcome in the ICU Resistance rates increasing Most data for use of antibiotics derive from studies in non-icu subjects and ignores unique ICU issues (eg fluid resuscitation, MV, changing renal fxn) How do we optimize antibiotic administration in the ICU?
Attributable Mortality by Causal Inference This was calculated as the difference between the observed ICUmortality and the ICU-mortality that would have been observed for the same population if VAP were prevented for all. Bekaert M, et al. Am J Respir Crit Care Med 2011;184:1133-1139.
Multi-State Model Indicates VAP Attributable Mortality of 8.1% at 120 Days 2873 patients from 12 French ICUs (1996-2007) Attributable mortality higher In surgical patients With intermediate SAPS II values With multi-organ dysfunction (LOD score) Nguile-Makao M, et al. ICM 2010;36:781-789.
Early Appropriate Therapy is Critical in NP 107 patients with VAP Mean time from diagnosis of VAP to initiation of appropriate therapy was 28.6 hr in delayed group vs. 12.5 hr in early group p < 0.01 p = 0.001 Iregui M, et al. Chest 2002;122:262-268.
Odds Ratio of Death (95% Confidence Interval) Appropriate Initial Therapy An earlier study of septic shock (n = 2,731) explicitly demonstrated the importance of antimicrobial timing 100 10 1 Time From Hypotension Onset (hr) Every hour s delay until appropriate therapy resulted in a 12% increase in mortality Compared with starting appropriate therapy within 1 hour of the onset of hypotension, the OR for mortality increased from 1.67 in Hour 2 to 92.54 with delays >36 hours Kumar A, et al. Crit Care Med. 2006;34:1589-1596.
First Understand your local problem with Resistance!
ECDC Surveillance Data - 2012 Proportion of 3rd gen. cephalosporins Resistant (R) Klebsiella pneumoniae Proportion of Carbapenems Resistant (R) Pseudomonas aeruginosa
ECDC Surveillance Data - 2012 MRSA
Klebsiella pneumoniae Antimicrobial Drug Resistance, United States, 1998 2010 CDC Prevalence of antimicrobial crossresistance among imipenemresistant Klebsiella pneumoniae isolates
Empiric Treatment Approaches for Pneumonia Guidelines-Based Treatment Combination Therapy/De-escalation Approach Adequate Dosing PK/PD Optimization Prolonged Infusion Duration Enhanced Diagnostics Aerosolized Antibiotic Administration
Current guidelines for the empirical treatment of HAP/VAP Barbier F, et al. Cur Opin Pulm Med 2013; 19:216-228.
IMPACT- HAP Are Guidelines Harmful? Kett DH, et al. Lancet ID 2011;11:181-189.
Kett DH, et al. Lancet ID 2011;11:181-189.
PK/ PD: Part of the Solution
Concentration (mg/l) Serum antibiotic levels over a dosing interval 0 Time (hours)
PK (Pharmacokinetics) Pharmacokinetics describes the concentration-time profile of a drug (in this case antibiotic) in the body
PD (Pharmacodynamics) Pharmacodynamics correlates the concentration of the antibiotic with its ability to kill or inhibit the target pathogen
PK-PD Relationship PK Dose concentration PD Concentration effect PK-PD Dose concentration effect Dose PK concentration PD effect PK-PD Relationship
Concentration Antimicrobial Pharmacodynamics C max :MIC Concentration-dependent: i.e. Aminoglycosides, Colistin AUC AUC:MIC Fluoroquinolones T > MIC Time-dependent: i.e. Beta-lactams MIC Time (hours)
conc. (mg/l) at 3 d ose (VAN BID 1g q12h) Current Vancomycin Dosing Recommendations 40 30 Clin Infect Dis. 2011 Feb 1;52(3):285-92. 20 10 0 0 6 12 Time (h)
But..
Increased Vancomycin Use Not Improving Rates of Bactericidal Activity in Pneumonia AUC/MIC ratio 400 MIC value 0.5mg/L (%) 1.0mg/L (%) 2.0mg/L (%) 500 mg IV Q12H 57 15 0.7 1000 mg IV Q12H 90 57 1.5 1500 mg IV Q12H 97 79 38 2000 mg IV Q12H 98 90 57 MIC = minimum inhibitory concentration AUC = area under the curve (exposure) Patel et al. CID. 2011;52(8):969-974
Increased Doses of Vancomycin Does Not Necessarily Improve Outcomes Percentage of Isolates with Vancomycin MIC 2.0 mg/ml Vancomycin Success Rates at Higher MICs are 5-fold Lower MSSA MRSA 2005 2006 0.5 mg/ml Success Rate 56% 2007 2008 1.0-2.0 mg/ml Success Rate 10% 2009 0% 2% 4% 6% 8% 10% 12% Hawser et al. International Journal of Antimicrobial Agents. 2011;37(3):219-24. 0% 10% 20% 30% 40% 50% 60% Sakoulas G et al. J Clin Microbiol. 2004;42:2398-2402
Clinical Outcome: Vancomycin MIC 2.69 (1.60,4.51) 1.64 (1.14,2.37) 0.01 0.1 1 10 100 0.01 0.1 1 10 100 Low MIC failure High MIC failure Low MIC mortality High MIC mortality Van Hal SJ et al. Clin Infect Dis 2012;54:755-71
Zephyr: Design Overview & Objective Design Overview Phase IV, randomized, double-blind, multicenter, international comparator-controlled study in MRSA HAP or HCAP Fixed-dose linezolid vs dose-optimized vancomycin Noninferiority study with nested superiority Study Objective To prospectively assess efficacy, safety, and tolerability of linezolid compared with vancomycin HAP, hospital-acquired pneumonia; HCAP, healthcare-associated pneumonia; MRSA, methicillin-resistant S. aureus. Wunderink RG, et al.linezolid in methicillin-resistant Staphylococcus aureus nosocomial pneumonia: A randomized, controlled trial. Clin Infect Dis. Advanced access published January 12, 2012, doi:10.1093/cid/cir895 29
Patients (%) With Clinical Cure Primary End Point: Clinical Cure at EOS (Per-Protocol Population) Clinical Cure Rate Statistically Significantly Higher With Linezolid than Vancomycin 100 80 60 40 57.6% P=.042 95% CI: 0.5, 21.6 46.6% 20 0 9 unknown patients were excluded from the analysis CI, confidence interval; IV, intravenous. 95/165 81/174 Linezolid 600 mg IV q12h Vancomycin 15 mg/kg IV q12h Wunderink RG, et al.linezolid in methicillin-resistant Staphylococcus aureus nosocomial pneumonia: A randomized, controlled trial. Clin Infect Dis. Advanced access published January 12, 2012, doi:10.1093/cid/cir895 30
Patients (%) With Clinical Response Clinical Response at EOS and EOT (Per-Protocol and mitt Populations) Linezolid Vancomycin 100 80 P=.042 95% CI:.5, 21.6 95% CI:.1, 19.8 95% CI: 4.9, 22.0 95% CI: 4.0, 20.7 83.3% 80.1% 69.9% 67.8% 60 40 57.6% 54.8% 46.6% 44.9% 20 0 95/165 81/174 102/186 92/205 150/180 130/186 161/201 145/214 Per-Protocol at EOS mitt at EOS Per-Protocol at EOT mitt at EOT Primary End Point Secondary End Points Wunderink RG, et al.linezolid in methicillin-resistant Staphylococcus aureus nosocomial pneumonia: A randomized, controlled trial. Clin Infect Dis. Advanced access published January 12, 2012, doi:10.1093/cid/cir895 31
Patients (%) With Nephrotoxicity Secondary End Point: Incidence of Nephrotoxicity (mitt Population) Laboratory Evidence of Nephrotoxicity* 40 30 Linozelid Vancomycin 20 18.2% 13.8% 16.2% 18.8% 10 8.4% 5.6% 0 Overall GFR <50 ml/min GFR >50 ml/min * 0.5-mg/mL increase in serum creatinine if normal at baseline, or 50% increase if abnormal at baseline. GFR, glomerular filtration rate. Wunderink RG, et al.linezolid in methicillin-resistant Staphylococcus aureus nosocomial pneumonia: A randomized, controlled trial. Clin Infect Dis. Advanced access published January 12, 2012, doi:10.1093/cid/cir895 32
Televancin Novel lipoglycopeptide Dual mechanism of action, high in vitro potency Approved in US for cssti and pneumonia EMA Treatment of adults with nosocomial pneumonia, including ventilator associated pneumonia Known or suspected to be caused by MRSA; Only in situations where it is known or suspected that other alternatives are not suitable
% Cure Telavancin 2 DBRCT Subjects HAP/VAP based on clinical criteria Interventions Van 1gm q 12 TLV 10mg/kg q 24 Endpoints Cure Mortality 100 80 60 40 20 0 Clinical Cure (AT) Clinical Cure (CE) TLV VAN Corey GR, et al. AAC. 3 Jan 2014 epub ahead of print.
Kaplan Meier survival curves showing 28-day survival in Study 0015, Study 0019, the aggregate AT population.
Kaplan Meier survival curves showing 28-day survival for the AT population (aggregated studies) in patients with CL CR <30 ml/min (A), CL CR 30 ml/min (B), CL CR <50 ml/min (C), and CL CR 50 ml/min (D)
Other changes in the critically ill patient affecting antibiotics Udy AA, et al. ICM. 2013; 39: 2070-82.
Renal Function Most agents cleared by the kidneys and common place to dose reduce based on estimated GFR However Estimated GFR poor correlate of true CrCl CrCl changes over time in critically ill What about if CrCl elevated?
Explanation of Augmented Renal Clearance ARC arises from interaction of: -Systemic inflammation -Physiologic reserve ARC noted in: -Young patients -Trauma patients Udy et al Clin Pharmacokinet 2010; 49:1-16
Trough concentration:mic β-lactam Underdosing in Patients with Augmented Renal Clearance (ARC)? ARC = supranormal glomerular filtration 100 ClCr > 130 ml/min/1.73m 2 Cockcroft Gault CrCl Most common in critically ill patients with: SIRS/Sepsis Trauma 10 1 50 100 150 200 250 300 350 ClCr (ml/min/1.73m 2 ) Baptista JP et al. Crit Care 2011;15:R139. Udy AA et al. Chest 2012;142:30-39.
Dosing Matters: Was This All Due to ARC? Infection type Treatment group Predicted mortality* (%) Non-VAP Ceftobiprole 18.5 18.8 Non-VAP Linezolid/Ceftazidime 19.0 21.2 Actual mortality (%) Ceftobiprole 500 mg q 8 vs Linezolid 600 mg q 12 hours & Ceftazidime 2 g q 8 VAP Ceftobiprole 24.2 33.7 VAP Linezolid/Ceftazidime 24.2 22.6 *Based on Knaus et al. Crit Care Med 1985;13:818 Study primary enrolled -Young patients with normal estimated renal function -Trauma patients Basilea (On File)
Clinical Cure & All-Cause 28-Day Mortality Doripenem Imipenem 7-day course 10- day course n N % n N % Diff (%) 95% CI Clinical cure rate MITT 36 79 45.6 50 88 56.8-11.2 ( -26.3; 3.8) ME 28 57 49.1 36 59 66.1-17.0 ( -34.7; 0.8) Creatinine clearance* (MITT) 150 ml/min 8 18 44.4 20 28 71.4-27.0 (-55.4; 1.4) 80-150 31 15 48.4 37 19 51.4-3.0-26.8; 20.9 >50 - <80 23 12 52.2 18 9 50.0 2.2-28.7; 33.0 >30-50 5 0 0 2 1 50.0-50.0 30 2 1 50.0 3 1 33.3 16.7 All cause 28-day mortality MITT 17 79 21.5 13 88 14.8 6.7 (-5.0; 18.5) MITT = Microbiological ITT, ME = Microbiologically Evaluable * Calculated using Cockcroft -Gault formulas relating serum creatinine with age & body weight Kollef, MH, et al. Crit Care 2012;16(6):R218.
Novel Dosing Approaches in the ICU: Extended Infusion DBRCT Continuous infusion betalactam vs intermittent bolus Subjects: severe sepsis (n=60) Primary Endpoint: Plasma drug conc above pathogen MIC on days 3 and 4 Secondary endpoint: Clinical response Dulhunty JM, et al. Clin Infect Dis 2013; 56: 236-44
Conclusions PK: PD relationships important in the ICU ICU patients are unique Consider ARC Consider novel dosing approaches Look for newer options on the horizon