1. 1 Developed by Consensus III Medical Expert Group : Gert Höffken, Universitat Dresden, Dresden, Germany George Karam, Louisiana State University Medical School, New Orleans, LA, USA Marin Kollef, Washington University School of Medicine, St. Louis, MO, USA Carlos Luna, University of Buenos Aires, Argentina Johan Maertens, University Hospital Gasthuisberg, Leuven, Belgium Michael Niederman, Winthrop University Hospital, Mineola, NY, USA David Paterson, University of Pittsburgh Medical School, PA, USA Jordi Rello, University Hospital Joan XXIII, Tarragona, Spain Jean-Louis Trouillet, Groupe Hospitalier PITIE SALPETRIERE, Paris, France De-Escalation Therapy ™ in Clinical Practice: Delivery of Effective and Responsible Antimicrobial Treatment Consensus III De-Escalation Therapy and the pinwheel symbol are trademarks of Merck & Co., Inc., Whitehouse Station, NJ, USA. TEN 2003-W-9415 SS

2. 2 An Art in Medicine Balance An Evidence-Based Problem: Mortality with Inadequate Therapy A Theoretical Dilemma: Concern of Resistance with Broad-Spectrum Therapy Evans RS et al. N Engl J Med 1998;338:232-238. Gruson D et al. Am J Respir Crit Care Med 2000;162:837-843. Raymond DP et al. Crit Care Med 2001;29:1101-1108. Clinical evidence showing lack of resistance with heterogeneous use of broad-spectrum therapy Copyright © 2003 Merck & Co., Inc., Whitehouse Station, NJ, USA. All rights reserved. 2-04 TEN 2002-W-9397-SS VISIT US ON THE WORLD WIDE WEB AT http://www.merck.comhttp://www.merck.com

3. 3 High Mortality with HAP and Severe Sepsis Included among the most frequent serious infections in the ICU are: –Hospital-acquired pneumonia (HAP) –Severe sepsis. –HAP and severe sepsis are associated with high mortality rates. Inadequate therapy for HAP and severe sepsis increases mortality. Kollef MH. Clin Infect Dis 2000;31(Suppl 4):S131-S138. Richards MJ et al. Crit Care Med 1999;27:887-892. Ibrahim EH et al. Chest 2000;118:146-155. Van der Poll T. Lancet Infect Dis 2001;1:165-174. Bernard GR et al. N Engl J Med 2001;344:699-709. Alvarez-Lerma F et al. Intensive Care Med 1996;22:387-394. Pfaller MA et al. Antimicrob Agents Chemother 2000;44:747-751. Garnacho-Montero J et al. Crit Care Med 2003;31:2742-2751.

4. 4 Mortality* Associated with Initial Inadequate Therapy in Critically Ill ICU Patients with HAP or Sepsis 0%20%40%60%80%100% Luna, 1997 Ibrahim, 2000*** Kollef, 1998 Harbarth, 2003*** Rello, 1997 Alvarez-Lerma, 1996** Initial adequate therapy Initial inadequate therapy *Mortality refers to crude or infection-related mortality. **Includes patients with HAP. ***Patients had blood stream infections rather than pneumonia as in the other studies. Alvarez-Lerma F et al. Intensive Care Med 1996;22:387-394. Luna CM et al. Chest 1997;111:676-685. Rello J et al. Am J Respir Crit Care Med 1997;156:196-200. Kollef MH et al. Chest 1998;113:412-420. Ibrahim EH at al. Chest 2000;118:146-155. Harbarth S et al. Am J Med 2003;115:529-535. Valles J et al. Chest 2003;123:1615-1624. Mortality Valles, 2003*** 24.7% 91% 37% 38% 15.6% 33.3% 60.8% 28.4% 61.9% 24% 39% 63% 31% 16.2%

5. 5 Defining Inadequate Therapy Inadequate therapy –“...the microbiological documentation of infection…that was not effectively treated at the time the causative microorganism and its antibiotic susceptibility were known…” 1 Other factors to consider in defining Inadequate therapy: 1,2 –Microbiologic data (including lack of consistently predicting outcome based on in vitro susceptibility) –Monotherapy versus combination therapy –Dose and dosing frequency –Penetration –Timing –Toxicity –Risk of influencing resistance –Prior antibiotic use 1. Kollef MH. Clin Infect Dis 2000;31(Suppl 4):S131-S138. 2. Kollef MH et al. Chest 1999;115:462-474.

6. 6 Delayed Therapy May Be Inadequate Therapy: Results from a Single-Center Study in VAP Early appropriate therapy, before bacteriologic data are known, leads to an improved outcome. ATB = antibiotic; BAL = bronchoalveolar lavage Adapted from Luna CM et al. Chest 1997;111:676-685. % Mortality 70% 91% 38% 71% p<0.01 p=NS

7. 7 De-Escalation Therapy™ Stage 1 Administering broad-spectrum antibiotic therapy to improve outcomes (decrease mortality, prevent organ dysfunction, and decrease length of hospital stay) Stage 2 Focusing on de-escalating as a means to minimize resistance and improve cost-effectiveness Note: In some patients, additional therapy to include pathogens not covered with the initial regimen may be necessary.

8. 8 Patients Who May Benefit from Empirical Broad-Spectrum Antimicrobial Therapy HAP VAP Bacteremia Severe sepsis (including bacterial and fungal pathogens) Severe community-acquired pneumonia Critically ill patients with serious infections, for example, patients with:

9. 9 Broad & Balance-spectrum activity Reliable efficacy Low potential for resistance/cross-resistance Favorable pK/pD Low endotoxin release Time-tested tolerability Consider imipenem your carbapenem of choice for patients with serious nosocomial infections: TIENAM Unsurpassed Experience and Time-Tested Reliability