1. Principles of Treating Infectious Illnesses in Critical Care: Focus on Antibiotic Resistance and Choice Slide Sub-Title Robert Owens, PharmD Gil Fraser, PharmD, FCCM University of Vermont College of Medicine and Maine Medical Center, Portland “ We shall now discuss in a little more detail the struggle for existence.” C Darwin 1859

3. Post-Antibiotic Era Mortality: What the Future Holds?

5. Mechanisms of Bacterial Resistance to Antibiotics

7. The Pharmacology of Infectious Diseases Involves Many Factors HOST BUG DRUG Nicolau DP Am J Man Care 1998:4(10 Suppl) S525-30

11. Correct Initial Choice of Abx Offers Survival Benefit Kollef MH, et al. Chest. 1998;113:412-420; Ibrahim EH, et al. Chest. 2000;118:146-155 Mortality (%) Initial Appropriate Therapy Luna et al Crude Mortality 0 20 40 60 80 100 Ibrahim et al Infection-Related Mortality Kollef et al Crude Mortality Rello et al Infection-Related Mortality Initial Inappropriate Therapy Luna CM, et al. Chest. 1997;111:676-685; Rello J, et al. Am J Respir Crit Care Med. 1997;156:196-200.

12. Targeted Approach to Antimicrobial Treatment When microbiologic data are known, narrow antibiotic coverage Kollef M. Why appropriate antimicrobial selection is important: Focus on outcomes. In: Owens RC Jr, Ambrose PG, Nightingale CH., eds. Antimicrobial Optimization: Concepts and Strategies in Clinical Practice . New York:Marcel Dekker Publishers, 2005:41-64.

15. 8 vs 15 Day Treatment of VAP No difference in outcome except if P. aeruginosa involved No. at risk 197 187 172 158 151 148 147 204 194 179 167 157 151 147 Probability of survival Days after Bronchoscopy P=0.65 JAMA 2003 290:2588 Antibiotic regimen 8 days 15 days

20. Antibiotic Pharmacology and the Pharmacodynamics of Bacterial Killing

21. Bacterial Targets for Antibiotics

22. Pharmacodynamics of Bacterial Killing Concentration-dependent (greater bacterial kill at higher concentrations) vs. Concentration-independent

23. The Pharmacodynamics of Bacterial Killing Concentration-Independent: Optimal kill defined by time over the minimum inhibitory concentration (T>MIC) T>MIC Concentration Time (hours) MIC Beta-lactams Vancomycin Clindamycin Macrolides

24. Meropenem 500 mg Administered as a 3 h Infusion Extends the Time Over the MIC vs a 0.5 h infusion Dandekar PK et al. Pharmacotherapy. 2003;23:988-991. MIC 0 2 4 6 8 0.1 1.0 10.0 100.0 Concentration (mcg/mL) Time (h) Rapid Infusion (30 min) Extended Infusion (3 h) Additional T>MIC gained

26. Selected Review of Specific Agents

28. Penicillin Resistance with Streptococcus pneumoniae in the United States 0 5 10 15 20 25 30 35 40 1979-87 1988-89 1990-91 1992-93 1994-95 1997-98 1999-00 Percent 5589 487 524 799 1527 1601 1531 1940 1828 35 15 17 19 30 34 33 45 44 2001-02 1980’s 1990’s 2002-03 2000’s Resistant (MICs > 2) Intermediate (MICs 0.12-1)

30. Oxacillin Bactericidal Activity

38. Alarming Increase in Rate of Quinolone Resistance in P. aerugniosa Fluoroquinolone-resistant Pseudomonas aeruginosa Non-Intensive Care Unit Patients Intensive Care Unit Patients Source: National Nosocomial Infections Surveillance (NNIS) System

39. Important Reduction in GI Tract Quinolone Absorption with Bi and Tri-Valent Cations

40. Vancomycin (also formerly known as Mississippi Mud) Name derived from the word “Vanquish”

49. Once-daily vs. Conventional Three-times Daily Aminoglycoside Regimens Optimizes Concentration-dependant Effect on Bacterial Kill Conventional (three-times daily regimen) Nicolau et al. Antimicrob Agents Chemother 1995;39:650–655 Concentration (mg/L) 0 8 14 4 6 10 12 Time (hours) 0 12 24 20 4 8 16 2 Once-daily regimen

53. Macrolide Resistance with Streptococcus pneumoniae in the United States 0 5 10 15 20 25 30 1979-87 1988-89 1990-91 1994-95 1997-98 1999-00 2001-02 Percent 2002-03

55. Antifungal Treatment Candida as a Pathogen in Nosocomial Bloodstream Infections in 49 US Hospitals * Surveillance and Control of Pathogens of Epidemiologic Importance. Adapted with permission from Edmond et al. Clin Infect Dis . 1999;29:239-244. The SCOPE* Program (1995-1998) 1 Coagulase-negative staphylococci 3908 31.9 21 2 Staphylococcus aureus 1928 15.7 25 3 Enterococci 1354 11.1 32 4 Candida species 934 7.6 40 No. of Crude Rank Pathogen Isolates % Mortality(%)

58. Efficacy: Fluconazole vs Conventional Amphotericin B in Nonneutropenic Patients With Candidemia BUN = blood urea nitrogen. Rex et al. N Engl J Med . 1994;331:1325-1330. Fluconazole (400 mg/d) Conventional Amphotericin B (0.5-0.6 mg/kg/d) Patients (%) Successful Outcome Elevation of BUN/ Serum Creatinine Hypokalemia Elevation of Liver Enzymes ( P =NS) ( P <.001) ( P =.006) ( P =.43) 70 79 37 2 10 2 10 14

59. Comparative Microbiologic Activity Candida albicans C. glabrata Fluconazole Resistant C. albicans Cryptococci Aspergillus spp. Fusarium spp. Zygomycetes Susceptible, dose-dependent Caspofungin Voriconazole Some cross-resistance No activity indicated in black C. krusei