Page 1 of 7. May and June 2012

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1 Page 1 of 7 CRITICAL CARE PHARMACOTHERAPY LITERATURE UPDATE May and June 2012 T his is a monthly review of select articles in the medical literature pertaining to pharmacotherapy used in critically ill patient populations. The content below is for information purposes only and is intended to highlight recent articles that may be of interest to those caring for patients in various intensive care or related settings. Though some core content from the publications is presented, the reader is encouraged to review each article in full for additional detail in order to fully interpret the study, its findings, and its applicability to practice. N W ew physicians, physician assistants, nurse practitioners, and others can now earn continuing medical education for reading the latest Critical Care Pharmacotherapy Updates free of charge! Each newsletter on the website offers partial AMA PRA Category 1 Credit(s). Go to to start earning credit! ant to subscribe to this newsletter? Go to click on Subscribe to our FREE Newsletter, and provide an e mail address at which you would not mind receiving our missive. You ll get an e mail from us with a couple of additional instructions once you re done with those, you ll be all set! CONTRIBUTORS Sarah Day, Pharm.D. (Doctors Hospital); Erin Frazee, Pharm.D. (Mayo); Deanna McMahon Horner, Pharm.D., BCPS (UCSF); Christine Lesch, Pharm.D. (NY Pres); Jessica Mercer, Pharm.D., BCPS (Bon Secours St. Francis); Heather Personett, Pharm.D. (Mayo) Editors: Peter Herout, Pharm.D., BCPS (CardinalHealth); Charles J Turck, Pharm.D., BCPS (UMass)

2 Page 2 of 7 CONTENTS Effects of Targeting Higher Vancomycin Trough Levels on Clinical Outcomes and Costs in a Matched Patient Cohort... 3 Active Surveillance Cultures of Methicillin Resistant S. aureus Ventilator Associated Pneumonia... 3 Antibiotic Strategies in Severe Nosocomial Sepsis: Why Do We Not De Escalate More Often?... 4 Macrolide Antibiotics and Survival in Patients with Acute Lung Injury... 5 Safety of Early Warfarin Resumption Following Burr Hole Drainage for Warfarin Associated Subacute or Chronic Subdural Hemorrhage... 5 A Randomized Trial of Tenecteplase Versus Alteplase for Acute Ischemic Stroke... 6 Other Recent Publications of Interest... 7

3 Page 3 of 7 EFFECTS OF TARGETING HIGHER VANCOMYCIN TROUGH LEVELS ON CLINICAL OUTCOMES AND COSTS IN A MATCHED PATIENT COHORT Kullar R, Davis SL, Taylor TN, et al. Pharmacotherapy. 2012;32: Study Question: What are the clinical outcomes and costs in patients treated with vancomycin trough goals of mg/l (per more recent clinical guidelines) as compared to patients with trough goals of 5 20 mg/l (treated prior to the release of the most recent guidelines)? Study Description: This was a retrospective, quasiexperimental study conducted from at a level I trauma center including all patients who received at least 72 h of vancomycin therapy for confirmed, complicated methicillin resistant Staphylococcus aureus (MRSA) bacteremia that would require dosing adequate to achieve trough levels of mg/l. Patients with MRSA pneumonia and those receiving empiric vancomycin therapy were excluded. Clinical outcomes and costs were compared between patients with confirmed MRSA bacteremia from with targeted trough levels of < 15mg/L (pre period phase) and with targeted trough levels of 15 20mg/L (post period phase). Results: A total of 200 patients (100 from each period) were matched according to predefined criteria. Pre period patients had significantly lower clinical success rates with vancomycin vs. postperiod patients (45% vs. 60%, p = 0.034). The pre period group also had higher overall median hospital costs as compared to the post period group ($32,754 vs. $27,709, p = 0.147). The median time from first positive blood culture until discharge or death (15 days vs days, p = 0.28) and median duration of vancomycin therapy (13 days vs. 8.5 days, p < 0.001) were both longer in the pre period group vs. postperiod group. The rate of nephrotoxicity was lower in the pre period group as compared to the postperiod group (15% vs. 18%). While that difference was not statistically significant (p = 0.85), patients who developed nephrotoxicity did have a significantly longer median length of stay (17 days vs. 14 day, p = 0.017). Nephrotoxicity was defined as at least two high serum creatinine values (an increase of 0.5 mg/dl or 50% increase from baseline during vancomycin therapy in the absence of a viable, alternative explanation. Conclusion(s): Higher vancomycin trough levels improved outcomes in patients with complicated MRSA bacteremia, and more aggressive dosing significantly decreased the overall duration of vancomycin therapy. Patients experiencing nephrotoxicity had a significantly longer hospital length of stay. Perspective: Despite higher drug and monitoring costs observed with a more aggressive vancomycin dosing regimen, the overall costs do not appear significantly different between the two groups. The overall duration of drug therapy was less in postperiod patients suggesting the potential for decreased morbidity and length of stay. ACTIVE SURVEILLANCE CULTURES OF METHICILLIN RESISTANT S. AUREUS VENTILATOR ASSOCIATED PNEUMONIA Chan JD, Dellit TH, Choudhuri JA, et al. Crit Care Med. 2012;40: Study Question: Can active surveillance cultures (ASCx) be used to predict the development of MRSA ventilator associated pneumonia (VAP)?

4 Page 4 of 7 Study Description: A prospective, observational study was conducted at a university affiliated level I burn and trauma center. Adult ICU patients were included if they required mechanical ventilation for 48 hours and met diagnostic criteria for VAP. MRSA ASCx were performed on all patients on admission to the ICU, once every 7 days, and at discharge from the ICU. ASCx were collected from nares, oropharynx, trachea, and any open wounds. Results: Twenty six (70%) patients presenting with MRSA VAP had previously documented MRSA colonization, while 4 (11%) patients were noted to be colonized on the same day as bronchoscopy. The MRSA ASCx performance characteristics were: a sensitivity of 70.3%, a specificity of 92%, a positive predictive value of 48.1%, and a negative predictive value of 96.7%. Conclusion(s): Based on the high specificity and negative predictive value of ASCx, the study s authors concluded that a negative ASC would exclude MRSA as a likely etiology of VAP at their institution. Perspective: Previous studies provide conflicting results in regards to ASCx utility in predicting VAP pathogens. Although this study found value in the MRSA ASCx as a predictive tool, the external validity is limited by its single center study design. Institutional MRSA VAP prevalence, surveillance technique, compliance rate with the components of the VAP bundle, patient population, and infection control practices are all factors with the potential to influence the generalizability of this study s results. ANTIBIOTIC STRATEGIES IN SEVERE NOSOCOMIAL SEPSIS: WHY DO WE NOT DE ESCALATE MORE OFTEN? Heenen S, Jacobs F, Vincent JL. Crit Care Med. 2012;40: Study Question: How are antibiotic de escalation recommendations being applied in ICU patients and what is the impact on patient outcomes? Study Description: This was a retrospective, singlecenter study that took place over one year. Included individuals were adults with hospital acquired severe sepsis or septic shock who received broadspectrum antibiotics for 3 days per provider preference and after discussion with infectious disease consultants. De escalation occurred when a single agent was discontinued or changed to an agent with a narrower spectrum of activity. Results: There were 169 initial episodes of nosocomial, severe sepsis included, 59% of which involved septic shock. Pulmonary and intrabdominal sources of infection comprised the majority of patients with culture positivity (77%), and antimicrobials that the study s authors deemed as appropriate were used in 84% of cases. Deescalation occurred in 46% of cases and most commonly discontinuation of (as opposed to a change in) antimicrobial agent. In multivariate modeling, significant predictors of de escalation were appropriate initial antimicrobial therapy (odds ratio [OR] 2.7; 95% confidence interval [CI] ) and initial monotherapy versus multi therapy (OR 0.17; 95% CI ). Conclusion(s): Even in the presence of multidisciplinary collaboration, antimicrobial deescalation occurs in less than half of nosocomial severe sepsis cases. Perspective: Antimicrobial de escalation in ICU patients is predicated on patient trajectory, culture positivity, microbiologic susceptibility patterns, practitioner comfort and diligence and, as reflected in this study, appropriateness of initial

5 Page 5 of 7 antimicrobials. Local rates of extended spectrum beta lactamase producing gram negative organisms, MRSA, and vancomycin resistant Enterococcus (VRE) are likely to affect the ability to de escalate antimicrobials, although these pathogens presented infrequently in this present study. MACROLIDE ANTIBIOTICS AND SURVIVAL IN PATIENTS WITH ACUTE LUNG INJURY Walkey AJ, Wiener RS. Chest. 2012;141: Study Question: Does an association exist between macrolide antibiotics and mortality in patients with acute lung injury (ALI)? Study Description: This study was a retrospective analysis of the Acute Respiratory Distress Syndrome Network (ARDSNet) Lisofylline and respiratory Management of Acute Lung Injury (LARMA) database. Patients were compared on the basis of whether they received a macrolide antibiotic within the first 60 h of recognition of ALI, and the primary outcome was 180 day survival. Results: A macrolide antibiotic, most commonly erythromycin, was used in 235 patients for a mean duration of 4 days; 188 patients included in the study did not receive a macrolide. On multivariate analysis, patients who received a macrolide antibiotics had a lower mortality rate (relative risk [RR] 0.46; 95% CI ; p = 0.028). The secondary outcome of duration on mechanical ventilation was also significantly shorter in patients who received a macrolide antibiotic. No similar effects were seen when analyzing other classes of antibiotics, including fluoroquinolones. Conclusion(s): The authors conclude that their study suggests an association between macrolide antibiotics and decreased mortality in patients with ALI in a manner that warrants further study. Perspective: This study supports the hypothesis that macrolide antibiotics may have a role in the treatment of patients with ALI. Although this analysis includes a larger population of human subjects than previously published studies on the topic, interpretation of results is limited by its retrospective nature, notably a lack of statistical power and protocol guidance for antimicrobial administration. Its results are hypothesis generating and support clinical trials examining the same question. SAFETY OF EARLY WARFARIN RESUMPTION FOLLOWING BURR HOLE DRAINAGE FOR WARFARIN ASSOCIATED SUBACUTE OR CHRONIC SUBDURAL HEMORRHAGE Yeon JY, Kong DS, Hong SC. J Neurotrauma. 2012;29: Study Question: Is it safe to restart warfarin early after burr hole drainage for warfarin associated subacute or chronic subdural hemorrhage (SDH)? Study Description: In this prospective, single arm, single center trial, patients were considered for inclusion if they met the following criteria: 1) premorbid warfarin therapy; 2) SDH requiring burrhole drainage; and 3) international normalized ratio (INR) > 1.5 at presentation. Fresh frozen plasma (FFP) and vitamin K were administered to correct INR prolongation to < 1.5 followed by burr hole SDH drainage. Post op CT scans were performed the day after surgery to assess for residual SDH or recurrent hemorrhage, and a drainage catheter was removed one to two days after surgery. The usual daily dose

6 Page 6 of 7 of warfarin was restarted 3 days after surgery to reach a target INR of 2.1, and a follow up CT scan was performed on post op day 7, and at 1, 3, and 6 months after surgery. Results: None of the patients had thromboembolic events within 1 month of surgery (primary efficacy outcome). In the primary safety outcome of incidence of recurrent SDH documented by CT scans within 1 month of surgery, 3 of the 19 patients (15.8%) were found to have recurrent SDH. There were no other intracranial hemorrhages, serious extracranial hemorrhages, or thromboembolic events in the remaining 19 patients during the 6 month study period. Conclusion(s): The authors conclude that restarting warfarin does not need to be delayed for more than 3 days following burr hole drainage for warfarinassociated SDH, particularly in patients with high thromboembolic risk. Perspective: This study s results are interesting, but it would be premature to change practice on their basis due to the study s limitations (small sample size, non comparative design, etc.). A RANDOMIZED TRIAL OF TENECTEPLASE VERSUS ALTEPLASE FOR ACUTE ISCHEMIC STROKE Parsons M, Spratt N, Bivard A, et al. N Engl J Med. 2012;366: Study Question: Is tenecteplase superior to alteplase for the treatment of ischemic stroke? Study Description: This study was a randomized, open label, phase IIb trial. Patients received computed tomographic perfusion and angiographic imaging within 6 hours and were included if imaging demonstrated significant diffusion/perfusion mismatch. Once patients met criteria, they were randomized to one of three groups: tenecteplase 0.25 mg/kg or 0.1 mg/kg or alteplase 0.9 mg/kg. The co primary outcomes were the percentage of the perfusion lesion that was reperfused within 24 h of treatment and the 24 h change in National Institutes of Health Stroke Scale (NIHSS) score. Among others, the secondary outcomes included excellent or good recovery at 90 days (modified Rankin scale score [mrss] of 0 2), symptomatic intracranial hemorrhage, and poor outcome (mrss of 5 or 6) or death at 90 days. Results: Seventy five patients were enrolled with a mean NIHSS of , and researchers observed no difference in time to receipt of treatment in the alteplase group and the pooled tenecteplase groups (2.7 vs 3.1 hours). The following benefits were associated with tenecteplase vs. alteplase: greater reperfusion (79.3% of patients vs. 55.4%; p = 0.004) and clinical improvement (NIHSS score improvement) at 24 hours (8.0 vs. 3.0; p < 0.001) as well as a reduced median infarct growth at 24 h (3 ml vs. 14 ml; p 0.04) and 90 day (2 ml vs. 12 ml; p 0.01) and a higher proportion of patients with an excellent or good recovery at 90 days (72% vs. 44%, p = 0.02). There was no statistical difference in safety endpoints. Conclusions: Tenecteplase was superior to alteplase for reperfusion and clinical improvement at 24 h as well as better recovery at 90 days without increased rates of intracranial hemorrhage. Perspective: Tenecteplase s longer half life and greater fibrin specificity may make is superior to alteplase. Another clinical trial is desirable to validate these findings.

7 Page 7 of 7 OTHER RECENT PUBLICATIONS OF INTEREST Chow AW, Benninger MS, Brook I, et al. IDSA Clinical Practice Guideline for Acute Bacterial Rhinosinusitis in Children and Adults. Clin Infect Dis. 2012;54:e72 e112. Devabhakthuni S, Armahizer MJ, Dasta JF, Kane Gill SL. Analgosedation: a Paradigm Shift in Intensive Care Unit Sedation Practice. Ann Pharmacother. 2012;46: EINSTEIN PE Investigators, Büller HR, Prins MH, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366: Hayden SJ. Anemia in Critical Illness: Insights into Etiology, Consequences and Management. Am J Resp Crit Care Med. 2012;185: Smith BS, Yogaratnam D, Levasseur Franklin KE, et al. Introduction to Drug Pharmacokinetics in the Critically Ill Patient. Chest. 2012;141: Vanek VW, Seidner DL, Allen P, et al. A.S.P.E.N. Position Paper: Clinical Role for Alternative Intravenous Fat Emulsions. Nutr Clin Pract. 2012;27: